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Targeting phosphodiesterase 4 as a potential therapy for Parkinson’s disease: a review

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Nongthombam Pooja Devi at Manipur University
Nongthombam Pooja Devi
Reena Haobam at Manipur University
Reena Haobam
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Abstract and Figures

Phosphodiesterases (PDEs) have become a promising therapeutic target for various disorders. PDEs are a vast and diversified family of enzymes that degrade cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which have several biochemical and physiological functions. Phosphodiesterase 4 (PDE4) is the most abundant PDE in the central nervous system (CNS) and is extensively expressed in the mammalian brain, where it catalyzes the hydrolysis of intracellular cAMP. An alteration in the balance of PDE4 and cAMP results in the dysregulation of different biological mechanisms involved in neurodegenerative diseases. By inhibiting PDE4 with drugs, the levels of cAMP inside the cells could be stabilized, which may improve the symptoms of mental and neurological disorders such as memory loss, depression, and Parkinson’s disease (PD). Though numerous studies have shown that phosphodiesterase 4 inhibitors (PDE4Is) are beneficial in PD, there are presently no approved PDE4I drugs for PD. This review presents an overview of PDE4Is and their effects on PD, their possible underlying mechanism in the restoration/protection of dopaminergic cell death, which holds promise for developing PDE4Is as a treatment strategy for PD. Methods on how these drugs could be effectively delivered to develop as a promising treatment for PD have been suggested.
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REVIEW
Molecular Biology Reports (2024) 51:510
https://doi.org/10.1007/s11033-024-09484-8
akinesia, postural reex abnormalities, gait disruption, etc.,
are common signs of PD [6]. Commonly used therapeutic
drugs like Levodopa (L-dopa) and DA agonists are bene-
cial for reversing motor dysfunction in PD, but they are not
as successful in restoring cognitive impairment [6]. L-dopa
reduces Parkinsonian-related motor impairments, but the
long-term use of this drug induces signicant side eects,
such as dyskinesia, that lead to a lower quality of life and
worsen the symptoms [7]. Overproduction of reactive oxy-
gen species (ROS) by L-dopa may further contribute to the
death of neurons [8]. Therefore, there is an urgent require-
ment for the exploration of therapeutic agents to get bet-
ter clinical outcomes. Selective death of DAergic neurons,
Lewy body formation from the abnormal aggregation of
α-synuclein, oxidative stress, and chronic neuroinamma-
tion are the main pathogenic hallmarks of PD [9, 10]. The
excessive degeneration and apoptosis of DAergic neurons
are hypothesized to result from a combination of factors,
such as genetic mutations, improper protein folding, oxida-
tive stress, neuroinammation, and neuronal excitotoxicity
[11–13]. However, the detailed mechanism and causes of
DAergic neuron degeneration remain uncertain [13]. So,
Introduction
Parkinson’s disease (PD) is a progressive neurodegenerative
disease marked by the loss of dopamine (DA) in the stria-
tum and a loss of dopaminergic (DAergic) neurons in the
substantia nigra pars compacta (SNpc) region of the brain,
which leads to problems with movement control and other
non-movement-related symptoms [1, 2]. Dopamine (DA), a
neurotransmitter produced by nerve cells in this region of the
brain, acts as a messenger between parts of the brain and ner-
vous system that serve to control and coordinate movement
[3]. PD is diagnosed when more than 50% of the DAergic
neurons have already degenerated, and 80% of the striatal
dopamine are lost [4]. About 2 to 3% of the population over
65 years has PD, making it the second most prevalent neu-
rodegenerative disorder [5]. Tremor, rigidity, bradykinesia,
Reena Haobam
reena_haobam@redimail.com
1 Department of Biotechnology, Manipur University,
Canchipur, Imphal 795003, India
Abstract
Phosphodiesterases (PDEs) have become a promising therapeutic target for various disorders. PDEs are a vast and diver-
sied family of enzymes that degrade cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate
(cGMP), which have several biochemical and physiological functions. Phosphodiesterase 4 (PDE4) is the most abundant
PDE in the central nervous system (CNS) and is extensively expressed in the mammalian brain, where it catalyzes the
hydrolysis of intracellular cAMP. An alteration in the balance of PDE4 and cAMP results in the dysregulation of dierent
biological mechanisms involved in neurodegenerative diseases. By inhibiting PDE4 with drugs, the levels of cAMP inside
the cells could be stabilized, which may improve the symptoms of mental and neurological disorders such as memory
loss, depression, and Parkinson’s disease (PD). Though numerous studies have shown that phosphodiesterase 4 inhibitors
(PDE4Is) are benecial in PD, there are presently no approved PDE4I drugs for PD. This review presents an overview of
PDE4Is and their eects on PD, their possible underlying mechanism in the restoration/protection of dopaminergic cell
death, which holds promise for developing PDE4Is as a treatment strategy for PD. Methods on how these drugs could be
eectively delivered to develop as a promising treatment for PD have been suggested.
Keywords Neurodegeneration · Phosphodiesterase 4 inhibitors · Oxidative stress · Apoptosis · Neuroinammation
Received: 8 December 2023 / Accepted: 26 March 2024 / Published online: 15 April 2024
© The Author(s), under exclusive licence to Springer Nature B.V. 2024
Targeting phosphodiesterase 4 as a potential therapy for Parkinson’s
disease: a review
Pooja DeviNongthombam1· ReenaHaobam1
1 3
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Four distinct genes-PDE4A, PDE4B, PDE4C, and PDE4D-encode the PDE4 isoforms, which share a highly conserved catalytic domain but exhibit functional diversity due to alternative splicing and different regulatory elements. These isoforms are classified into long, short, super-short, and dead-short forms based on the presence and length of two upstream conserved regions (UCR1 and UCR2), which modulate enzymatic activity through post-translational modifications, notably phosphorylation by protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) [7][8][9]. ...
Molecular Properties of Phosphodiesterase 4 and Its Inhibition by Roflumilast and Cilomilast
Article
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Phosphodiesterase 4 (PDE4) catalyzes cyclic adenosine monophosphate (cAMP) hydrolysis, playing a crucial role in the cAMP signaling pathway. cAMP is a secondary messenger involved in numerous physiological functions, such as inflammatory responses, immune responses, neural activity, learning, and memory. PDE4 inhibition is important for controlling anti-inflammatory and neuroprotective effects. In this review, we provide a comprehensive overview of the molecular functions and properties of human PDE4s. The study presents detailed sequence information for the PDE4 isoforms and the structural properties of the catalytic domain in members of the PDE4 family. We also review the inhibitory effects of the PDE4 inhibitors roflumilast and cilomilast related to respiratory diseases in PDE4. The crystal structures of PDE4 in complex with roflumilast and cilomilast are also analyzed. This review provides useful information for the future design of novel PDE4 inhibitors.
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... However, the compound has < tenfold selectivity for different PDE4 isoforms (Wang et al. 2012). Rolipram reverses memory deficits in mouse models of AD and provides cognitive benefit in rodent models of stroke, traumatic brain injury, and Huntington's disease (Wang et al. 2012;Fusco and Paldino 2017;Tibbo et al. 2019;Nongthombam and Haobam 2024). A study in 3-month old APP/PS1 transgenic mice that rolipram reverses deficits in hippocampal long-term potentiation, contextual fear conditioning, and the Morris water maze (Cong et al. 2023). ...
Connecting dots: Preclinical foundations to clinical realities of PDE4 inhibitors in Alzheimer's disease
Article
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  • Jan 2025
  • InflammoPharmacology
Alzheimer's Disease (AD), a progressive and age-associated neurodegenerative disorder, is primarily characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles. Despite advances in targeting Aβ-mediated neuronal damage with anti-Aβ antibodies, these treatments provide only symptomatic relief and fail to address the multifactorial pathology of the disease. This necessitates the exploration of novel therapeutic approaches and a deeper understanding of molecular signaling mechanisms underlying AD. Phosphodiesterases (PDEs), particularly Phosphodiesterase 4 (PDE4), play a pivotal role in regulating cyclic adenosine monophosphate (cAMP), a key molecule involved in memory consolidation and cognitive function. PDE4 inhibitors have demonstrated potential in enhancing memory and cognition in preclinical models of AD by modulating cAMP signaling. However, their clinical translation has been limited due to challenges such as adverse effects, narrow therapeutic windows, and low specificity in mechanism of action. This review bridges the gap between preclinical discoveries and clinical applications of PDE4 inhibitors in AD. It highlights preclinical evidence supporting the neuroprotective and anti-inflammatory effects of PDE4 inhibitors while addressing challenges in their clinical development, including issues of safety, efficacy, and disease-specific targeting. By integrating findings from both preclinical and clinical studies, we provide a comprehensive understanding of the therapeutic potential of PDE4 inhibitors in AD. Furthermore, this review outlines future research directions aimed at optimizing PDE4 inhibition strategies for AD treatment, offering a roadmap to translate foundational insights into clinical realities.
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... Therefore, new forms of PD treatment are constantly being sought to alleviate the negative effects of both these phenomena. Recently, the attention of researchers has focused on examining the effectiveness of phosphodiesterase (PDE) inhibitors in the treatment of PD [11][12][13][14][15]. ...
The Effect of Chronic Treatment with the Inhibitor of Phosphodiesterase 5 (PDE5), Sildenafil, in Combination with L-DOPA on Asymmetric Behavior and Monoamine Catabolism in the Striatum and Substantia Nigra of Unilaterally 6-OHDA-Lesioned Rats
Article
Full-text available
The use of phosphodiesterase inhibitors in the treatment of Parkinson’s disease is currently widely discussed. The study aimed to investigate the impact of acute and chronic treatment with the phosphodiesterase 5 inhibitor, sildenafil, at low and moderate doses of 2 mg/kg and 6 mg/kg, and L-DOPA (12.5 mg/kg), alone or in combination, on asymmetric behavior and dopamine (DA) and serotonin metabolism in the striatum and substantia nigra of unilaterally 6-OHDA-lesioned rats. Acute administration of sildenafil at both tested doses jointly with L-DOPA significantly increased the number of contralateral rotations during a 2 h measurement compared to L-DOPA alone. The effect of a lower dose of sildenafil combined with L-DOPA was much greater in the second hour of measurement. However, the acute combined administration of a higher dose of sildenafil with L-DOPA resulted in an immediate and much stronger increase in the number of contralateral rotations compared to L-DOPA alone, already visible in the first hour of measurement. Interestingly, the chronic combined administration of 2 mg/kg of sildenafil and L-DOPA significantly reduced the number of contralateral rotations, especially during the first hour of measurement, compared to the long-term treatment with L-DOPA alone. Such an effect was not observed after the long-term combined treatment of a higher dose of sildenafil and L-DOPA compared to L-DOPA alone. The concentration of DA in the ipsilateral striatum and substantia nigra after the last combined chronic dose of sildenafil (2 or 6 mg/kg) and L-DOPA (12.5 mg/kg) was significantly higher than after L-DOPA alone. In spite of much stronger increases in the DA concentration in the ipsilateral striatum and substantia nigra, the number of contralateral rotations was reduced in the group of rats treated with the combination of 2 mg/kg sildenafil and L-DOPA compared to the group receiving L-DOPA alone. Moreover, the combined treatment with a low dose of sildenafil and L-DOPA had an opposite effect on DA catabolism, as assessed by DOPAC/DA and HVA/DA indexes, and these indexes were reduced in the ipsilateral striatum but increased in the contralateral striatum and substantia nigra compared to the treatment with L-DOPA alone. The results of the present study show that the addition of a low dose of a PDE5 inhibitor to the standard L-DOPA therapy differently modulates rotational behavior, the tissue DA concentration and its catabolism in the striatum and substantia nigra.
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Recent developments of phosphodiesterase inhibitors: Clinical trials, emerging indications and novel molecules
Article
Full-text available
  • Nov 2022
The phosphodiesterase (PDE) enzymes, key regulator of the cyclic nucleotide signal transduction system, are long-established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a particularly high number of clinical trials involving PDE inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 87 agents with PDE-inhibiting capacity, of which 85 interact with PDE enzymes as primary target. We provide an overview of the clinical drug development with focus on the current clinical uses, novel molecules and indications, highlighting relevant clinical studies. We found that the bulk of current clinical uses for this class of therapeutic agents are chronic obstructive pulmonary disease (COPD), vascular and cardiovascular disorders and inflammatory skin conditions. In COPD, particularly, PDE inhibitors are characterised by the compliance-limiting adverse reactions. We discuss efforts directed to appropriately adjusting the dose regimens and conducting structure-activity relationship studies to determine the effect of structural features on safety profile. The ongoing development predominantly concentrates on central nervous system diseases, such as schizophrenia, Alzheimer’s disease, Parkinson’s disease and fragile X syndrome; notable advancements are being also made in mycobacterial infections, HIV and Duchenne muscular dystrophy. Our analysis predicts the diversification of PDE inhibitors’ will continue to grow thanks to the molecules in preclinical development and the ongoing research involving drugs in clinical development.
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An Overview of PDE4 Inhibitors in Clinical Trials: 2010 to Early 2022
Article
Full-text available
Since the early 1980s, phosphodiesterase 4 (PDE4) has been an attractive target for the treatment of inflammation-based diseases. Several scientific advancements, by both academia and pharmaceutical companies, have enabled the identification of many synthetic ligands for this target, along with the acquisition of precise information on biological requirements and linked therapeutic opportunities. The transition from pre-clinical to clinical phase was not easy for the majority of these compounds, mainly due to their significant side effects, and it took almost thirty years for a PDE4 inhibitor to become a drug i.e., Roflumilast, used in the clinics for the treatment of chronic obstructive pulmonary disease. Since then, three additional compounds have reached the market a few years later: Crisaborole for atopic dermatitis, Apremilast for psoriatic arthritis and Ibudilast for Krabbe disease. The aim of this review is to provide an overview of the compounds that have reached clinical trials in the last ten years, with a focus on those most recently developed for respiratory, skin and neurological disorders.
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Targeting phosphodiesterase 4 as a therapeutic strategy for cognitive improvement
Article
  • Nov 2022
  • BIOORG CHEM
Phosphodiesterase 4 (PDE4), the largest member of PDE family, is highly expressed in mammalian brain. It selectively hydrolyzes the second messenger cyclic adenosine monophosphate (cAMP), a correlate of brain functions including learning, memory and cognitive abilities. Its inhibition is beneficial to counteract cognitive deficits. Thus, targeting PDE4 may be a viable strategy for cognitive improvement. Currently, many PDE4 inhibitors have been discovered but with a great hurdle in clinical development due to adverse effects such as emesis. Analysis of PDE4 subtypes and discovery of subtype specific regulators indicate therapeutic benefits with improved safety in preclinical and clinical models. Herein, we summarize PDE4 structure, describe PDE4 mediated signaling pathways, review the role of individual PDE4 subtypes and discuss the development of PDE4 inhibitors for cognitive improvement, trying to give an insight into the strategy for cognitive improvement with PDE4 inhibitors in future.
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Lipid nanoparticles strategies to modify pharmacokinetics of central nervous system targeting drugs: Crossing or circumventing the blood–brain barrier (BBB) to manage neurological disorders
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  • Aug 2022
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The main limitation to the success of central nervous system (CNS) therapies lies in the difficulty for drugs to cross the blood-brain barrier (BBB) and reach the brain. Regarding its structure and enzymatic complexity, crossing the BBB is a challenge, although several alternatives have been identified. For instance, the use of drugs encapsulated in lipid nanoparticles has been described as one of the most efficient approaches to bypass the BBB, as they allow the passage of drugs through this barrier, improving brain bioavailability. In particular, solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) have been a focus of research related to drug delivery to the brain. These systems provide protection of lipophilic drugs, improved delivery and bioavailability, having a major impact on treatments outcomes. In addition, the use of lipid nanoparticles administered via routes that transport drugs directly into the brain seems a promising solution to avoid the difficulties in crossing the BBB. For instance, the nose-to-brain route has gained considerable interest, as it has shown efficacy in 3D human nasal models and in animal models. This review addresses the state of the art on the use of lipid nanoparticles to modify the pharmacokinetics of drugs employed in the management of neurological disorders. A description of the structural components of the BBB, the role of the neurovascular unit and limitations for drugs to entry into the CNS is first addressed, along with the developments to increase drug delivery to the brain, with a special focus on lipid nanoparticles. In addition, the obstacle of BBB complexity in the creation of new effective drugs for the treatment of the most prevalent neurological disorders is also addressed. Finally, the proposed strategies for lipid nanoparticles to reach the CNS, crossing or circumventing the BBB, are described. Although promising results have been reported, especially with the nose-to-brain route, they are still ongoing to assess its real efficacy in vivo in the management of neurological disorders.
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α-mangostin derivative 4e as a PDE4 inhibitor promote proteasomal degradation of alpha-synuclein in Parkinson's disease models through PKA activation
Article
  • Apr 2022
  • PHYTOMEDICINE
Background Parkinson's disease (PD) is a multi-factorial neurodegenerative disease affecting motor function of patients. The hall markers of PD are dopaminergic neuron loss in the midbrain and the presence of intra-neuronal inclusion bodies mainly composed of aggregation-prone protein alpha-synuclein (α-syn). Ubiquitin-proteasome system (UPS) is a multi-step reaction process responsible for more than 80% intracellular protein degradation. Impairment of UPS function has been observed in the brain tissue of PD patients. PDE4 inhibitors have been shown to activate cAMP-PKA pathway and promote UPS activity in Alzheimer's disease model. α-mangostin is a natural xanthonoid with broad biological activities, such as antioxidant, antimicrobial and antitumour activities. Structure-based optimizations based on α-mangostin produced a potent PDE4 inhibitor, 4e. Herein, we studied whether 4e could promote proteasomal degradation of α-syn in Parkinson's disease models through PKA activation. Methods cAMP Assay was conducted to quantify cAMP levels in samples. Model UPS substrates (Ub-G76V-GFP and Ub-R-GFP) were used to monitor UPS-dependent activity. Proteasome activity was investigated by short peptide substrate, Suc-LLVY-AMC, cleavage of which by the proteasome increases fluorescence sensitivity. Tet-on WT, A30P, and A53T α-syn-inducible PC12 cells and primary mouse cortical neurons from A53T transgenic mice were used to evaluate the effect of 4e against α-syn in vitro. Heterozygous A53T transgenic mice were employed to assess the effect of 4e on the clearance of α-syn in vivo, and further validations were applied by western blotting and immunohistochemistry. Results Taken together, α-mangostin derivative 4e, a PDE4 inhibitor, efficiently activated the cAMP/PKA pathway in neuronal cells, and promoted UPS activity as evidenced by enhanced degradation of UPS substrate Ub-G76V-GFP and Ub-R-GFP, as well as elevated proteasomal enzyme activity. Interestingly, 4e dramatically accelerated degradation of inducibly-expressed WT and mutant α-syn in PC12 cells, in a UPS dependent manner. Besides, 4e consistently activated PKA in primary neuron and A53T mice brain, restored UPS inhibition and alleviated α-syn accumulation in the A53T mice brain. Conclusions 4e is a natural compound derived highly potent PDE4 inhibitor. We revealed its potential effect in promoting UPS activity to degrade pathogenic proteins associated with PD.
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Phosphodiesterase‑4 inhibitors: a review of current developments (2013-2021)
Article
  • Jan 2022
Introduction Cyclic nucleotide phosphodiesterase 4 (PDE4) is responsible for the hydrolysis of cAMP, which has become an attractive therapeutic target for lung, skin, and severe neurological diseases. Nowadays, intensive efforts have been made to develop diverse PDE4 inhibitors for treatment of COPD, asthma and other human diseases, and four small-molecule PDE4 inhibitors have been approved by the FDA. Here, we review the current status of development of PDE4 inhibitors since 2013 and discuss the applicability of novel medicinal-chemistry strategies for identifying more efficient and safer inhibitors. Areas covered This review summarizes the clinical development of PDE4 inhibitors from 2013-2021, focused on their pharmacophores, the strategies to reduce the side effects of PDE4 inhibitors and the development of subfamily selective PDE4 inhibitors. Expert opinion To date, great efforts have been made in the development of PDE4 inhibitors, and researchers have established a comprehensive preclinical database and collected some promising data from clinical trials. Although four small-molecule PDE4 inhibitors have been approved by FDA for the treatment of human diseases up to now, further development of other reported PDE4 inhibitors with strong potency has been hampered due to the occurrence of severe side effects. There are currently three main strategies for overcoming the dose limitation and systemic side effects, which provide new opportunities for the clinical development of new PDE4 inhibitors.
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Roflupram attenuates α-synuclein-induced cytotoxicity and promotes the mitochondrial translocation of Parkin in SH-SY5Y cells overexpressing A53T mutant α-synuclein
Article
  • Jan 2022
  • TOXICOL APPL PHARM
We have previously shown that inhibition of cAMP-specific 3′,5′-cyclic phosphodiesterase 4 (PDE4) protects against cellular toxicity in neuronal cells. Since α-synuclein (α-syn) toxicity contributes to the neurodegeneration of Parkinson's disease (PD). The aim of this study was to explore the effects and mechanisms of PDE4 on α-syn-induced neuronal toxicity. Using mutant human A53T α-syn overexpressed SH-SY5Y cells, we found that PDE4B knockdown reduced cellular apoptosis. Roflupram (ROF, 20 μM), a selective PDE4 inhibitor, produced similar protective effects and restored the morphological alterations of mitochondria. Mechanistic studies identified that α-syn enhanced the phosphorylation of Parkin at Ser131, followed by the decreased mitochondrial translocation of Parkin. Whereas both PDE4B knockdown and PDE4 inhibition by ROF blocked the effects of α-syn on Parkin phosphorylation and mitochondrial translocation. Moreover, PDE4 inhibition reversed the increase in the phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by α-syn. ROF treatment also reduced the binding of p38 MAPK to Parkin. Consistently, overexpression of PDE4B blocked the roles of ROF on p38 MAPK phosphorylation, Parkin phosphorylation, and the subsequent mitochondrial translocation of parkin. Furthermore, PDE4B overexpression attenuated the protective role of ROF, as evidenced by reduced mitochondria membrane potential and increased cellular apoptosis. Interestingly, ROF failed to suppress α-syn-induced cytotoxicity in the presence of a protein kinase A (PKA) inhibitor H-89. Our findings indicate that PDE4 facilitates α-syn-induced cytotoxicity via the PKA/p38 MAPK/Parkin pathway in SH-SY5Y cells overexpressing A53T mutant α-synuclein. PDE4 inhibition by ROF is a promising strategy for the prevention and treatment of α-syn-induced neurodegeneration.
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Roflupram protects against rotenone-induced neurotoxicity and facilitates α-synuclein degradation in Parkinson’s disease models
Article
  • Sep 2021
We have previously shown that roflupram (ROF) protects against MPP+-induced neuronal damage in models of Parkinson’s disease (PD). Since impaired degradation of α-synuclein (α-syn) is one of the key factors that lead to PD, here we investigated whether and how ROF affects the degradation of α-syn in rotenone (ROT)-induced PD models in vivo and in vitro. We showed that pretreatment with ROF (10 μM) significantly attenuated cell apoptosis and reduced the level of α-syn in ROT-treated SH-SY5Y cells. Furthermore, ROF significantly enhanced the lysosomal function, as evidenced by the increased levels of mature cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1) through increasing NAD+/NADH and the expression of sirtuin 1 (SIRT1). Pretreatment with an SIRT1 inhibitor selisistat (SELI, 10 μM) attenuated the neuroprotection of ROF, ROF-reduced expression of α-syn, and ROF-increased expression levels of LAMP1 and mature CTSD. Moreover, inhibition of CTSD by pepstatin A (20 μM) attenuated ROF-reduced expression of α-syn. In vivo study was conducted in mice exposed to ROT (10 mg·kg−1·d−1, i.g.) for 6 weeks; then, ROT-treated mice received ROF (0.5, 1, or 2 mg·kg−1·d−1; i.g.) for four weeks. ROF significantly ameliorated motor deficits, which was accompanied by increased expression levels of tyrosine hydroxylase, SIRT1, mature CTSD, and LAMP1, and a reduced level of α-syn in the substantia nigra pars compacta. Taken together, these results demonstrate that ROF exerts a neuroprotective action and reduces the α-syn level in PD models. The mechanisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.
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Are Lysosomes Potential Therapeutic Targets for Parkinson's Disease?
Article
  • Aug 2021
  • CNS NEUROL DISORD-DR
Background Parkinson´s disease (PD) is the second most common neurodegenerative disorder, affecting 2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy bodies (LBs). Recently, genome-wide association studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. Aim The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.
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