Department of Molecular Neuroscience and Reta Lila Weston Institute of Neurological Studies, Institute of Neurology, University College London and the National Hospital for Neurology and Neurosurgery, London, UK.
The Lancet (Impact Factor: 45.22). 07/2009; 373(9680):2055-66. DOI: 10.1016/S0140-6736(09)60492-X
Parkinson's disease is a common progressive bradykinetic disorder that can be accurately diagnosed. It is characterised by the presence of severe pars-compacta nigral-cell loss, and accumulation of aggregated alpha-synuclein in specific brain stem, spinal cord, and cortical regions. The main known risk factor is age. Susceptibility genes including alpha-synuclein, leucine rich repeat kinase 2 (LRRK-2), and glucocerebrosidase (GBA) have shown that genetic predisposition is another important causal factor. Dopamine replacement therapy considerably reduces motor handicap, and effective treatment of associated depression, pain, constipation, and nocturnal difficulties can improve quality of life. Embryonic stem cells and gene therapy are promising research therapeutic approaches.
"To this end, we compared 24 h urinary sucralose and the sucralose/lactulose ratio in patients with Parkinson's disease that we have previously shown to have significantly increased intestinal permeability using 24 h urinary sucralose as a marker of gut leakiness . Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging, and is projected to affect nearly 10 million citizens of the world's most populous countries by 2030  . We have previously published intestinal permeability data for newly diagnosed Parkinson's disease (PD) patients and BMI/age-matched healthy controls using the same orally administered four sugar cocktail and analysis of 12 h urine samples for lactulose and mannitol and 24 h urinary sucralose as described above in Materials and methods section . "
"The common symptomatic feature of PD is bradykinesia, tremor, rigidity abnormalities in gait, and posture. The hallmark pathology of PD is accumulation of í µí»¼-synuclein, the main component of Lewy bodies in midbrain dopaminergic neurons      . Examination of Lewy bodies revealed the presence of not only í µí»¼-synuclein, but a variety of other proteins including, neurofilaments , ubiquitinated proteins, and several HSPs (HSP70 and HSP90) . "
[Show abstract][Hide abstract] ABSTRACT: The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer's disease, tauopathies, and Huntington's diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell.
BioMed Research International 10/2014; 2014:495091. DOI:10.1155/2014/495091 · 3.17 Impact Factor
"Parkinson's disease is a common neurodegenerative disease mainly characterized by severe loss of dopaminergic neurons in the substantia nigra pars compacta and by the formation of -synuclein positive aggregates (Lees et al., 2009). Nigral neuron degeneration and consequent decrease in dopaminergic striatal innervation result in classic Parkinson's disease motor symptoms. "
[Show abstract][Hide abstract] ABSTRACT: GTP cyclohydrolase 1, encoded by the GCH1 gene, is an essential enzyme for dopamine production in nigrostriatal cells. Loss-of-function mutations in GCH1 result in severe reduction of dopamine synthesis in nigrostriatal cells and are the most common cause of DOPA-responsive dystonia, a rare disease that classically presents in childhood with generalized dystonia and a dramatic long-lasting response to levodopa. We describe clinical, genetic and nigrostriatal dopaminergic imaging ([123I]N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl) tropane single photon computed tomography) findings of four unrelated pedigrees with DOPA-responsive dystonia in which pathogenic GCH1 variants were identified in family members with adult-onset parkinsonism. Dopamine transporter imaging was abnormal in all parkinsonian patients, indicating Parkinson's disease-like nigrostriatal dopaminergic denervation. We subsequently explored the possibility that pathogenic GCH1 variants could contribute to the risk of developing Parkinson's disease, even in the absence of a family history for DOPA-responsive dystonia. The frequency of GCH1 variants was evaluated in whole-exome sequencing data of 1318 cases with Parkinson's disease and 5935 control subjects. Combining cases and controls, we identified a total of 11 different heterozygous GCH1 variants, all at low frequency. This list includes four pathogenic variants previously associated with DOPA-responsive dystonia (Q110X, V204I, K224R and M230I) and seven of undetermined clinical relevance (Q110E, T112A, A120S, D134G, I154V, R198Q and G217V). The frequency of GCH1 variants was significantly higher (Fisher's exact test P-value 0.0001) in cases (10/1318 = 0.75%) than in controls (6/5935 = 0.1%; odds ratio 7.5; 95% confidence interval 2.4-25.3). Our results show that rare GCH1 variants are associated with an increased risk for Parkinson's disease. These findings expand the clinical and biological relevance of GTP cycloydrolase 1 deficiency, suggesting that it not only leads to biochemical striatal dopamine depletion and DOPA-responsive dystonia, but also predisposes to nigrostriatal cell loss. Further insight into GCH1-associated pathogenetic mechanisms will shed light on the role of dopamine metabolism in nigral degeneration and Parkinson's disease.
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