Characterization of Brain Lysosomal Activities in GBA-Related and Sporadic Parkinson’s Disease and Dementia with Lewy Bodies

Moors, Tim; Paciotti, Silvia; Ingrassia, Angela; Quadri, Marialuisa; Breedveld, Guido J.; Tasegian, Anna; Chiasserini, Davide; Eusebi, Paolo; Durán-Pacheco, Gonzalo; Kremer, Thomas; Calabresi, Paolo; Bonifati, Vincenzo; Parnetti, Lucilla; Beccari, Tommaso; Berg, Wilma D. J. van de

doi:10.1007/s12035-018-1090-0

Cited by 112 publications

(114 citation statements)

References 57 publications

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

“…Previously, we could show that PD patients carrying a GBA1 mutation (PD GBA ) also present reduced CSF levels of total alpha‐synuclein compared to PD patients with GBA1 wild type . Histopathological studies in PD and DLB report reduced GCase activity paralleled by alpha‐synuclein pathology in brains of GBA1 mutation carriers …”

Section: Discussionmentioning

confidence: 97%

Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha‐synuclein profile

et al. 2019

View full text Add to dashboard Cite

Background Patients with dementia with Lewy bodies reveal a variable pathology including alpha‐synuclein, amyloid‐beta, and Tau. Mutations in GBA1 are specifically associated with synucleinopathies. PD patients with GBA1 mutations show reduced CSF levels of total alpha‐synuclein. Objective Whether GBA1 mutations are associated with a CSF alpha‐synuclein profile in dementia with Lewy bodies. Methods Screening of the GBA1 gene and single‐nucleotide polymorphisms in SNCA rs356220, APOE rs429358, and MAPT rs1052587 as well as CSF levels of total alpha‐synuclein, amyloid‐beta1‐42, total‐Tau, phospho‐Tau, and neurofilament light chain were assessed in 100 dementia with Lewy bodies and 39 controls cross‐sectionally. Results Severity of GBA1 mutations was associated with a younger age at onset and higher prevalence of rapid eye movement sleep behavior disorder. CSF levels of total alpha‐synuclein were lowest in DLBGBA_pathogenic compared to DLBGBA_mild and DLBGBA_wildtype. Conclusion Similar to PD, pathogenic GBA1 mutations seem to be associated with CSF alpha‐synuclein profiles in dementia with Lewy bodies. That might be useful for patient stratification for specific alpha‐synuclein–lowering compounds. © 2019 International Parkinson and Movement Disorder Society

show abstract

Section: Discussionmentioning

confidence: 97%

Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha‐synuclein profile

et al. 2019

View full text Add to dashboard Cite

show abstract

“…To what extent CSF profiles of alpha‐synuclein might reflect the underlying pathology in the brain is unclear. Histopathological studies in PD report reduced GCase activity paralleled by alpha‐synuclein pathology in the brains of GBA1 mutation carriers . Following this mechanistic link between GBA1 mutations and alpha‐synuclein, it is tempting to speculate whether the reduced CSF levels of total alpha‐synuclein observed in the PD patients with severe GBA1 mutations might reflect alpha‐synuclein accumulation in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…Histopathological studies in PD report reduced GCase activity paralleled by alpha-synuclein pathology in the brains of GBA1 mutation carriers. [16][17][18] Following this mechanistic link between GBA1 mutations and alpha-synuclein, it is tempting to speculate whether the reduced CSF levels of total alpha-synuclein observed in the PD patients with severe GBA1 mutations might reflect alpha-synuclein accumulation in the brain. In this line of evidence, larger cohort studies in PD report total CSF levels of alpha-synuclein to be decreased with disease severity.…”

Section: Discussionmentioning

confidence: 99%

Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha‐Synuclein Profiles

et al. 2019

View full text Add to dashboard Cite

Background Mutations in the gene glucocerebrosidase (GBA1) are specifically associated with alpha‐synucleinopathies, namely, Parkinson's disease (PD) and dementia with Lewy bodies. As disease‐modifying treatment options such as alpha‐synuclein lowering compounds are under way, patient stratification according to alpha‐synuclein‐specific enrichment strategies, possibly reflected by cerebrospinal fluid (CSF) profiles, is a much needed prerequisite. Objective Are GBA1 mutations associated with a CSF alpha‐synuclein profile in PD? Methods Screening of the GBA1 gene and analysis of CSF levels of total alpha‐synuclein were performed in 80 PDGBA, 80 PDGBA_wildtype and 39 healthy controls cross‐sectionally. Subgroup analyses based on mutation severity was done for PDGBA. Results Patients carrying severe GBA1 mutations showed (1) an earlier age at onset, (2) more pronounced cognitive decline and higher prevalence of rapid eye movement sleep behavior disorder, and (3) reduced CSF levels of total alpha‐synuclein. Conclusion The effects of GBA1 mutations on CSF alpha‐synuclein profiles and phenotypical characteristics seem dependent on GBA1 mutation severity. © 2019 International Parkinson and Movement Disorder Society

show abstract

“…Reduced GCase activity was also found in the cingulate cortex of PD patients without GBA1 mutations . Moors and colleagues found significantly decreased GCase activity in the SN of both PD and DLB patients; a similar, though not significant, trend was also observed in the frontal cortex and putamen. In this series, CTSD activity was significantly decreased in the frontal cortex of DLB and PD patients, both in GBA1 mutation carriers and noncarriers.…”

Section: The Issue Of Alp Alterations In Sporadic Pdmentioning

confidence: 88%

“…In brain tissue, GCase activity and content have been shown to be reduced in the SN and other brain regions in different studies, both in GBA1 mutation carriers and sporadic PD patients . Importantly, Murphy and colleagues showed that the reduced activity is more evident at the early PD stage, and that the brain regions in which GCase activity is most affected are also those in which α‐syn accumulates the most.…”

Section: The Issue Of Alp Alterations In Sporadic Pdmentioning

confidence: 99%

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

et al. 2019

Self Cite

View full text Add to dashboard Cite

The accumulation and misfolding of α‐synuclein (α‐syn) represent the main pathological hallmark of PD. Overexpression of α‐syn and failure of cellular protein degradation systems play a major role in α‐syn aggregation. The discovery of PD‐associated genes related to the autophagic‐lysosomal pathway, such as VPS35, LRRK2, GBA1, SMPD1, GALC, ASAH1, SCARB2, CTSD, CTSB, and GLA, confirms the involvement of cellular clearance systems dysfunction in PD pathogenesis. Of importance, lysosomal enzyme activity is altered both in genetic and sporadic PD. Decreased lysosomal enzymes activities were measured in the same brain regions where α‐syn accumulates, suggesting that a crosstalk between α‐syn aggregation and autophagic‐lysosomal impairment may exist. The understanding of autophagic‐lysosomal pathway dysfunctions’ role in the pathogenesis and progression of synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, the evidences and mechanisms of the reciprocal relation between autophagic‐lysosomal pathway impairment and misfolded α‐syn aggregation and propagation are reviewed, together with the most promising compounds targeting autophagic‐lysosomal pathway restoration as a disease‐modifying strategy for PD treatment. © 2019 International Parkinson and Movement Disorder Society

show abstract

Characterization of Brain Lysosomal Activities in GBA-Related and Sporadic Parkinson’s Disease and Dementia with Lewy Bodies

Cited by 112 publications

References 57 publications

Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha‐synuclein profile

Dementia with lewy bodies: GBA1 mutations are associated with cerebrospinal fluid alpha‐synuclein profile

Parkinson's Disease: Glucocerebrosidase 1 Mutation Severity Is Associated with CSF Alpha‐Synuclein Profiles

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

Contact Info

Product

Resources

About