We and others have described the neurodegenerative disorder caused by G51D SNCA mutation which shares characteristics of Parkinson's disease (PD) and multiple system atrophy (MSA). The objective of ...this investigation was to extend the description of the clinical and neuropathological hallmarks of G51D mutant SNCA-associated disease by the study of two additional cases from a further G51D SNCA kindred and to compare the features of this group with a SNCA duplication case and a H50Q SNCA mutation case.
All three G51D patients were clinically characterised by parkinsonism, dementia, visual hallucinations, autonomic dysfunction and pyramidal signs with variable age at disease onset and levodopa response. The H50Q SNCA mutation case had a clinical picture that mimicked late-onset idiopathic PD with a good and sustained levodopa response. The SNCA duplication case presented with a clinical phenotype of frontotemporal dementia with marked behavioural changes, pyramidal signs, postural hypotension and transiently levodopa responsive parkinsonism. Detailed post-mortem neuropathological analysis was performed in all cases. All three G51D cases had abundant α-synuclein pathology with characteristics of both PD and MSA. These included widespread cortical and subcortical neuronal α-synuclein inclusions together with small numbers of inclusions resembling glial cytoplasmic inclusions (GCIs) in oligodendrocytes. In contrast the H50Q and SNCA duplication cases, had α-synuclein pathology resembling idiopathic PD without GCIs. Phosphorylated α-synuclein was present in all inclusions types in G51D cases but was more restricted in SNCA duplication and H50Q mutation. Inclusions were also immunoreactive for the 5G4 antibody indicating their highly aggregated and likely fibrillar state.
Our characterisation of the clinical and neuropathological features of the present small series of G51D SNCA mutation cases should aid the recognition of this clinico-pathological entity. The neuropathological features of these cases consistently share characteristics of PD and MSA and are distinct from PD patients carrying the H50Q or SNCA duplication.
Abstract
Background
The apolipoprotein E (
APOE
) gene exists in three isoforms in humans:
APOE2, APOE3
and
APOE4
.
APOE4
causes structural and functional alterations in normal brains, and is the ...strongest genetic risk factor of the sporadic form of Alzheimer’s disease (LOAD). Research on
APOE4
has mainly focused on the neuronal damage caused by defective cholesterol transport and exacerbated amyloid-β and Tau pathology. The impact of
APOE4
on non-neuronal cell functions has been overlooked. Astrocytes, the main producers of ApoE in the healthy brain, are building blocks of neural circuits, and Ca
2+
signaling is the basis of their excitability. Because
APOE4
modifies membrane-lipid composition, and lipids regulate Ca
2+
channels, we determined whether
APOE4
dysregulates Ca
2+
signaling in astrocytes.
Methods
Ca
2+
signals were recorded in astrocytes in hippocampal slices from
APOE3
and
APOE4
gene targeted replacement male and female mice using Ca
2+
imaging. Mechanistic analyses were performed in immortalized astrocytes. Ca
2+
fluxes were examined with pharmacological tools and Ca
2+
probes.
APOE3
and
APOE4
expression was manipulated with GFP-
APOE
vectors and
APOE
siRNA. Lipidomics of lysosomal and whole-membranes were also performed.
Results
We found potentiation of ATP-elicited Ca
2+
responses in
APOE4
versus
APOE3
astrocytes in male, but not female, mice. The immortalized astrocytes modeled the male response, and showed that Ca
2+
hyperactivity associated with
APOE4
is caused by dysregulation of Ca
2+
handling in lysosomal-enriched acidic stores, and is reversed by the expression of
APOE3
, but not of
APOE4
, pointing to loss of function due to
APOE4
malfunction. Moreover, immortalized
APOE4
astrocytes are refractory to control of Ca
2+
fluxes by extracellular lipids, and present distinct lipid composition in lysosomal and plasma membranes.
Conclusions
Immortalized
APOE4
versus
APOE3
astrocytes present: increased Ca
2+
excitability due to lysosome dysregulation, altered membrane lipidomes and intracellular cholesterol distribution, and impaired modulation of Ca
2+
responses upon changes in extracellular lipids. Ca
2+
hyperactivity associated with
APOE4
is found in astrocytes from male, but not female, targeted replacement mice. The study suggests that, independently of Aβ and Tau pathologies, altered astrocyte excitability might contribute to neural-circuit hyperactivity depending on
APOE
allele, sex and lipids, and supports lysosome-targeted therapies to rescue
APOE4
phenotypes in LOAD.
Abstract Leucine-rich repeat kinase 2 ( LRRK2 ) mutation is the most common cause of genetic-related parkinsonism and is usually associated with Lewy body pathology; however, tau, α-synuclein, and ...ubiquitin pathologies have also been reported. We report the case of a patient carrying the LRRK2 G2019S mutation and a novel heterozygous variant c.370C>G, p.Q124E in exon 4 of the microtubule-associated protein tau ( MAPT ). The patient developed parkinsonism with good levodopa response in her 70s. Neuropathological analysis revealed nigral degeneration and Alzheimer-type tau pathology without Lewy bodies. Immunohistochemical staining using phospho-TDP-43 antibodies identified occasional TDP-43 pathology in the hippocampus, temporal neocortex, striatum, and substantia nigra. However, TDP-43 pathology was not identified in another 4 archival LRRK2 G2019S cases with Lewy body pathology available in the Queen Square Brain Bank. Among other published cases of patients carrying LRRK2 G2019S mutation, only 3 were reportedly evaluated for TDP-43 pathology, and the results were negative. The role of the MAPT variant in the clinical and pathological manifestation in LRRK2 cases remains to be determined.
•Mutations in the ROC, COR and Kinase domain of LRRK2 alter the autophagic response to starvation.•LC3-I/II ratio following starvation is altered by mutations, as well as p62 and WIPI2 positive ...puncta.•This occurs independently of any alteration in downstream targets of mTORC1.
LRRK2 is one of the most important genetic contributors to Parkinson’s disease (PD). Point mutations in this gene cause an autosomal dominant form of PD, but to date no cellular phenotype has been consistently linked with mutations in each of the functional domains (ROC, COR and Kinase) of the protein product of this gene. In this study, primary fibroblasts from individuals carrying pathogenic mutations in the three central domains of LRRK2 were assessed for alterations in the autophagy/lysosomal pathway using a combination of biochemical and cellular approaches. Mutations in all three domains resulted in alterations in markers for autophagy/lysosomal function compared to wild type cells. These data highlight the autophagy and lysosomal pathways as read outs for pathogenic LRRK2 function and as a marker for disease, and provide insight into the mechanisms linking LRRK2 function and mutations.
The high levels of serine (S) and threonine (T) residues within the Presenilin 1 (PS1) N-terminus and in the large hydrophilic loop region suggest that the enzymatic function of PS1/γ-secretase can ...be modulated by its 'phosphorylated' and 'dephosphorylated' states. However, the functional outcome of PS1 phosphorylation and its significance for Alzheimer's disease (AD) pathogenesis is poorly understood. Here, comprehensive analysis using FRET-based imaging reveals that activity-driven and Protein Kinase A-mediated PS1 phosphorylation at three domains (domain 1: T74, domain 2: S310 and S313, domain 3: S365, S366, and S367), with S367 being critical, is responsible for the PS1 pathogenic 'closed' conformation, and resulting increase in the Aβ42/40 ratio. Moreover, we have established novel imaging assays for monitoring PS1 conformation in vivo, and report that PS1 phosphorylation induces the pathogenic conformational shift in the living mouse brain. These phosphorylation sites represent potential new targets for AD treatment.
The Hereditary Spastic Paraplegias are a group of neurodegenerative diseases characterized by spasticity and weakness in the lower body. Owing to the combination of genetic diversity and variable ...clinical presentation, the Hereditary Spastic Paraplegias are a strong candidate for protein-protein interaction network analysis as a tool to understand disease mechanism(s) and to aid functional stratification of phenotypes. In this study, experimentally validated human data were used to create a protein-protein interaction network based on the causative genes. Network evaluation as a combination of topological analysis and functional annotation led to the identification of core proteins in putative shared biological processes, such as intracellular transport and vesicle trafficking. The application of machine learning techniques suggested a functional dichotomy linked with distinct sets of clinical presentations, indicating that there is scope to further classify conditions currently described under the same umbrella-term of Hereditary Spastic Paraplegias based on specific molecular mechanisms of disease.
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•A bioinformatic study of the Hereditary Spastic Paraplegias using protein networks.•Human and manually curated protein-protein interaction data acquired using PINOT.•Intracellular transport and vesicle trafficking are suggested as disease mechanisms.•Machine learning techniques propose a patient clustering.
Bioinformatics; Biological sciences; Molecular network; Network;
Progressive multifocal leukoencephalopathy (PML) is an opportunistic brain infection with few treatment options and poor survival when reversal of the underlying immune dysfunction is not achievable. ...JC polyomavirus reactivation resulting in PML can rarely complicate chimeric antigen receptor T‐cell (CAR‐T) therapy. We describe successful treatment of PML with Programmed death‐1 (PD‐1) blockade using pembrolizumab, 4 months following axicabtagene ciloleucel. Radiological features of immune reconstitution inflammatory syndrome without clinical deterioration were seen. Evidence of anti‐viral immune reconstitution by in vitro detection of JC‐specific T‐cells and sustained neurological recovery in this patient suggest PD‐1 blockade may be an effective treatment approach for PML post‐CAR‐T.
Over the past decade, the importance of the propagation of amyloidogenic proteins such as α-synuclein and tau in the pathogenesis of neurodegenerative diseases has been supported by numerous ...neuropathological and experimental studies. While these proteins behave similarly to prions, recent evidence suggests the existence of fundamental differences, as they can propagate in the absence of endogenous template, they do not exhibit a strict ‘strain’ behavior, and they may not be transmissible between individuals. We therefore propose to name these proteins ‘prionoids’. In this review we critically assess the extent of the overlap between these two entities and evaluate how the propagation of prionoids can fit into the wider system dysfunction seen in the brains of patients with Alzheimer’s and Parkinson’s diseases.
There is evidence that tau can propagate with strain-like properties.
Tau can spread from cell to cell without requiring the presence of endogenous template.
The initiation of tau seeding and aggregation starts by phase transition from liquid to solid state.
Soluble toxic species of Aβ can initiate and enhance tau seeding.
There is not strong evidence supporting the iatrogenic transmission of Alzheimer’s and Parkinson’s diseases.
There is some evidence that α-synuclein pathology can start from the enteric nervous system and then spread to the brain.
α-Synuclein can be released from cells following a USP19-dependent procedure called misfolding-associated protein secretion (MAPS).
Recent genetic studies suggest that Alzheimer’s and Parkinson’s diseases are caused by a multisystem dysfunction.
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