Maria Grazia Spillantini

Maria Grazia Spillantini
University of Cambridge | Cam · Department of Clinical Neurosciences

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314
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Publications

Publications (314)
Article
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In 2017, it was 200 years since James Parkinson published 'An Essay on the Shaking Palsy' and 20 years since α-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson's disease and dementia with Lewy bodies as the third major synucleinopathy. Here, we describe the work that led to the identification of α-synuclein...
Article
MGS is supported by the UK Medical Research Council, Alzheimer’s Research UK, Gates International, Astra Zeneca, Cambridge Biomedical Centre, Addenbrooke’s Hospital Trust, the National Centre for the Replacement, Refinement and Reduction of Animals in Research and Horizon 2020 IMPRiND. MG is an Honorary Professor in the Department of Clinical Neuro...
Article
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Current therapeutic strategies to treat neurodegenerative diseases, such as alpha-synucleinopathies, aim at enhancing the amount of drug reaching the brain. Methods proposed, such as intranasal administration, should be able to bypass the blood brain barrier (BBB) and even when directly intracerebrally injected they could require a carrier to enhan...
Article
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We develop an approach to tag proteomes synthesized by specific cell types in dissociated cortex, brain slices, and the brains of live mice. By viral-mediated expression of an orthogonal pyrrolysyl-tRNA synthetase-tRNAXXX pair in a cell type of interest and providing a non-canonical amino acid with a chemical handle, we selectively label neuronal o...
Article
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In many neurodegenerative disorders, familial forms have provided important insights into the pathogenesis of their corresponding sporadic forms. The first mutations associated with frontotemporal lobar degeneration (FTLD) were found in the microtubule-associated protein tau (MAPT) gene on chromosome 17 in families with frontotemporal degeneration...
Article
Full-text available
Since the discovery of the microtubule-associated protein Tau (MAPT) over 40 years ago, most studies have focused on Tau’s role in microtubule stability and regulation, as well as on the neuropathological consequences of Tau hyperphosphorylation and aggregation in Alzheimer’s disease (AD) brains. In recent years, however, research efforts identifie...
Article
Full-text available
Microtubule-associated protein tau aggregates constitute the characteristic neuropathological features of several neurodegenerative diseases grouped under the name of tauopathies. It is now clear that the process of tau aggregation is associated with neurodegeneration. Several transgenic tau mouse models have been developed where tau progressively...
Article
Full-text available
Since the discovery of the microtubule-associated protein Tau (MAPT) over 40 years ago, most studies have focused on Tau’s role in microtubule stability and regulation, as well as on the neuropathological consequences of Tau hyperphosphorylation and aggregation in Alzheimer’s disease (AD) brains. In recent years, however, research efforts identifie...
Article
Microtubule-associated protein tau aggregates constitute the characteristic neuropathological features of several neurodegenerative diseases grouped under them name of tauopathies. It is now clear that the process of tau aggregation is associated with neurodegeneration. Several transgenic tau mouse models have been developed where tau progressively...
Article
Full-text available
Mutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson's disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson's disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mu...
Article
Chondroitin sulphate proteoglycans (CSPGs) are the main active component of perineuronal nets (PNNs). Digestion of the glycosaminoglycan chains of CSPGs with chondroitinase ABC or transgenic attenuation of PNNs leads to prolongation of object recognition memory and activation of various forms of plasticity in the adult CNS. The inhibitory propertie...
Article
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Since 2009, evidence has accumulated to suggest that Tau aggregates form first in a small number of brain cells, from where they propagate to other regions, resulting in neurodegeneration and disease. Propagation of Tau aggregates is often called prion-like, which refers to the capacity of an assembled protein to induce the same abnormal conformati...
Poster
Aims Glucocerebrosidase (GBA) is a lysosomal enzyme, which degrades glucocerebrosides, neuronal membrane components. Its functional impairment is causative for Gaucher’s disease. Such impairment also leads to chronic lysosomal stress, and thereby to a reduced α-synuclein clearance, possibly bringing about an α-synucleinopathy. In this project, hete...
Article
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In 2017, it is two hundred years since James Parkinson provided the first complete clinical description of the disease named after him, fifty years since the introduction of high-dose D,L-DOPA treatment and twenty years since ?-synuclein aggregation came to the fore. In 1998, multiple system atrophy joined Parkinson?s disease and dementia with Lewy...
Article
Full-text available
Background—Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer’s disease (AD) and Parkinson’s disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and ide...
Article
Parkinson's disease is the second most common neurodegenerative disorder, with only partial symptomatic therapy and no mechanism-based therapies. The accumulation and aggregation of α-synuclein is causatively linked to the sporadic form of the disease, which accounts for 95% of cases. The pathology is a result of a gain of toxic function of misfold...
Article
Full-text available
The validation of tau radioligands could improve the diagnosis of frontotempo-ral lobar degeneration and the assessment of disease-modifying therapies. Here, we demonstrate that binding of the tau radioligand [ 18 F]AV-1451 was significantly abnormal in both magnitude and distribution in a patient with familial frontotemporal dementia due to a MAPT...
Article
Full-text available
The validation of tau radioligands could improve the diagnosis of frontotempo-ral lobar degeneration and the assessment of disease-modifying therapies. Here, we demonstrate that binding of the tau radioligand [ 18 F]AV-1451 was significantly abnormal in both magnitude and distribution in a patient with familial frontotemporal dementia due to a MAPT...
Article
Full-text available
Abnormalities of tau protein are central to the pathogenesis of Progressive Supranuclear Palsy whilst haplotype variation of the tau gene MAPT influences the risk of Parkinson's disease and Parkinson’s disease dementia. We assessed whether regional MAPT expression might be associated with selective vulnerability of global brain networks to neurodeg...
Article
Multiple neurodegenerative disorders with tau pathology are characterized by the loss of memory and cognitive decline that can be associated with other symptoms including olfactory alterations that are often regarded as an early symptom of the diseases. Here we have investigated whether olfactory dysfunction is present in the P301S human tau transg...
Article
A new methodology is reported that allows a better control of the synthesis of polymeric core–shell nanocapsules. These nanocapsules were made of biocompatible polymers, obtained from poly(ethylene glycol)diacrylate and poly(ethylene glycol) methyl ether methacrylate, and were used as carrier for curcumin as therapeutic agent. The impact of manufac...
Article
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Unlabelled: Tauopathies are neurodegenerative diseases characterized by intraneuronal inclusions of hyperphosphorylated tau protein and abnormal expression of brain-derived neurotrophic factor (BDNF), a key modulator of neuronal survival and function. The severity of both these pathological hallmarks correlate with the degree of cognitive impairme...
Article
Parkinson's disease (PD), PD dementia (PDD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) are the most common synucleinopathies. The ordered assembly of α-synuclein leading from a soluble, lipid-bound, to an insoluble, filamentous protein underlies these disorders. Fibrils formed from α-synuclein (Lewy pathology) are seen in br...
Article
Although the physiological function of α-synuclein is not fully understood, it has been suggested to primarily localize to the presynaptic terminals of mature neurons, where it fulfills roles in synaptic function and plasticity. Based on current knowledge, α-synuclein (αSYN) is thought to be involved in maintaining neurotransmitter homeostasis by r...
Article
The validation of tau radioligands could improve the diagnosis of frontotempo-ral lobar degeneration and the assessment of disease-modifying therapies. Here, we demonstrate that binding of the tau radioligand [ 18 F]AV-1451 was significantly abnormal in both magnitude and distribution in a patient with familial frontotemporal dementia due to a MAPT...
Article
Full-text available
Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule-associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau-induce...
Article
Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule-associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau-induce...
Chapter
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Neurodegenerative diseases lead to significant morbidity and mortality. Although medical care for other disorders (e.g., cardiovascular disease and cancer) has improved, neurodegenerative diseases have become more prevalent as the population ages. Understanding of the scientific underpinnings of neurodegenerative diseases has advanced greatly over...
Article
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Featured Article : Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease. Neuron 1989;3:519–26.3 Alzheimer disease (AD)4 is characterized by 2 kinds of abundant abnormal filamentous lesions, neuritic...
Article
View largeDownload slide Twenty years ago McCarthy et al. described frontotemporal dementia parkinsonism linked to chromosome 17 (FTDP-17). They later identified a tau mutation (+14) in the exon/intron 10 splice site stem loop. Eleven of 12 predicted stem loop mutations were subsequently discovered. The authors now describe another Irish family wi...
Article
Background: Advanced Parkinson's disease (PD) is characterized by massive degeneration of nigral dopaminergic neurons, dramatic motor and cognitive alterations, and presence of nigral Lewy bodies, whose main constituent is α-synuclein (α-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overe...
Article
BACKGROUND: Advanced Parkinson's disease (PD) is characterized by massive degeneration of nigral dopaminergic neurons, dramatic motor and cognitive alterations, and presence of nigral Lewy bodies, whose main constituent is α-synuclein (α-syn). However, the synaptic mechanisms underlying behavioral and motor effects induced by early selective overex...
Article
Full-text available
Tauopathies, such as Alzheimer's disease, some cases of frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy, are characterized by aggregates of the microtubule-associated protein tau, which are linked to neuronal death and disease development and can be caused by mutations in the MAPT gene. Six tau isoforms are pre...
Article
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The main neuropathological features of Parkinson's disease (PD) are dopaminergic nigrostriatal neuron degeneration and intraneuronal and intraneuritic proteinaceous inclusions named Lewy bodies and Lewy neurites, mainly composed of α-synuclein (α-syn). The neuronal phosphoprotein synapsin III, is a pivotal regulator of dopamine (DA) neuron synaptic...
Article
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Huntington's disease is a neurodegenerative disorder caused by an abnormal CAG repeat expansion within exon 1 of the huntingtin gene HTT. While several genetic modifiers, distinct from the Huntington's disease locus itself, have been identified as being linked to the clinical expression and progression of Huntington's disease, the exact molecular m...
Article
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Identification of fluorescent dyes that label filamentous protein aggregates characteristic of neurodegenerative disease, such as β-amyloid and tau in Alzheimer’s disease (AD), in a live cell culture system has previously been a major hurdle. Here we show that pentameric formyl thiophene acetic acid (pFTAA) fulfils this function in living neurons c...
Article
Alpha-synuclein (α-syn) is the main protein component of Lewy bodies (LBs), that together with nigrostriatal dopamine neuron loss constitute typical pathological hallmarks of Parkinson's disease (PD). Glutamate N-methyl-d-aspartate receptors (NMDAR) abnormalities, peculiarly involving NR2B-containing NMDAR, have been observed the brain of PD patien...
Article
Full-text available
Parkinson's disease (PD) is an insidious and incurable neurodegenerative disease, and represents a significant cost to individuals, carers, and ageing societies. It is defined at post-mortem by the loss of dopamine neurons in the substantia nigra together with the presence of Lewy bodies and Lewy neurites. We examine here the role of α-synuclein an...
Article
The majority of neuroanatomical and chemical studies of the olfactory bulb have been performed in small rodents, such as rats and mice. Thus, this study aimed to describe the organisation and the chemical neuroanatomy of the main olfactory bulb (MOB) in paca, a large rodent belonging to the Hystricomorpha suborder and Caviomorpha infraorder. For th...
Article
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It has been proposed that tau aggregation confined to entorhinal cortex and hippocampus, with no or only minimal Aβ deposition, should be considered as a 'primary age-related tauopathy' (PART) that is not integral to the continuum of sporadic Alzheimer disease (AD). Here, we examine the evidence that PART has a pathogenic mechanism and a prognosis...
Article
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Alzheimer's disease is the most prevalent tauopathy and cause of dementia. We investigate the hypothesis that reactivation of plasticity can restore function in the presence of neuronal damage resulting from tauopathy. We investigated two models with tau hyperphosphorylation, aggregation and neurodegeneration: a transgenic mouse model in which the...
Article
Accumulation and aggregation of alpha-synuclein in cortical and hippocampal areas is a pathological sign for dementia with Lewy bodies (DLB) and Parkinson's disease with dementia. However the mechanisms of alpha-synuclein triggered cellular dysfunction leading to the development of memory impairment is not clear. We have created a mouse model of DL...
Article
Full-text available
Parkinson's disease is one of several neurodegenerative diseases associated with a misfolded, aggregated and pathological protein. In Parkinson's disease this protein is alpha-synuclein and its neuronal deposits in the form of Lewy bodies are considered a hallmark of the disease. In this review we describe the clinical and experimental data that ha...
Article
Background Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, diff erential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder.
Article
Full-text available
BACKGROUND: Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes-MAPT, GRN, and C9orf72-have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. METHODS:...
Article
Parkinson's disease (PD) is neuropathologically characterized as an alpha-synucleinopathy. Alpha-synuclein-containing inclusions are stained as Lewy bodies and Lewy neurites in the brain, which are the pathological hallmark of PD. However, alpha-synuclein-containing inclusions in PD are not restricted to the central nervous system, but are also fou...
Conference Paper
Full-text available
Neurodegenerative diseases, including Alzheimer disease, Parkinson disease, and many others, lead to significant morbidity and mortality. As medical care for other disorders (e.g., cardiovascular disease and cancer) has improved and people are living longer, neurodegenerative diseases have become more prevalent because age is a major risk factor fo...
Article
Full-text available
Filaments made of alpha-synuclein form the characteristic Lewy pathology in Parkinson's and other diseases. The formation of alpha-synuclein filaments can be reproduced in vitro by incubation of recombinant protein, but the filament growth is very slow and highly variable and so unsuitable for fast high throughput anti-aggregation drug screening. T...
Article
Full-text available
Frontotemporal lobar degeneration (FTLD) consists of a group of neurodegenerative diseases characterized by behavioural and executive impairment, language disorders and motor dysfunction. About 20-30 % of cases are inherited in a dominant manner. Mutations in the microtubule-associated protein tau gene (MAPT) cause frontotemporal dementia and parki...
Article
Full-text available
Intracellular tau aggregates are the neuropathological hallmark of several neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and cases of frontotemporal dementia, but the link between these aggregates and neurodegeneration remains unclear. Neuronal models recapitulating the main features of tau pathology are...