Analysis of age-related changes in psychosine metabolism in the human brain

Marshall, M. Scott; Jakubauskas, Benas; Bogue, Wil; Stoskute, Monika; Hauck, Zane; Rue, Emily; Nichols, Matthew; DiAntonio, Lisa L.; Breemen, Richard B. van; Kordower, Jeffrey H.; Saavedra-Matiz, Carlos A.; Bongarzone, Ernesto R.

doi:10.1371/journal.pone.0193438

Cited by 23 publications

(27 citation statements)

References 42 publications

(49 reference statements)

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“…Further supporting a role of GALC in the onset of PD, a recent study revealed reduced GALC activity and associated sphingolipid accumulation in sporadic PD patients, when compared to healthy controls . Interestingly, GALC activity was also reduced in aging, which is the strongest risk factor for PD.…”

Section: Galactosylceramidase (Galc)mentioning

confidence: 99%

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

2019

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Lysosomal storage disorders comprise a clinically heterogeneous group of autosomal‐recessive or X‐linked genetic syndromes caused by disruption of lysosomal biogenesis or function resulting in accumulation of nondegraded substrates. Although lysosomal storage disorders are diagnosed predominantly in children, many show variable expressivity with clinical presentations possible later in life. Given the important role of lysosomes in neuronal homeostasis, neurological manifestations, including movement disorders, can accompany many lysosomal storage disorders. Over the last decade, evidence from genetics, clinical epidemiology, cell biology, and biochemistry have converged to implicate links between lysosomal storage disorders and adult‐onset movement disorders. The strongest evidence comes from mutations in Glucocerebrosidase, which cause Gaucher's disease and are among the most common and potent risk factors for PD. However, recently, many additional lysosomal storage disorder genes have been similarly implicated, including SMPD1, ATP13A2, GALC, and others. Examination of these links can offer insight into pathogenesis of PD and guide development of new therapeutic strategies. We systematically review the emerging genetic links between lysosomal storage disorders and PD. © 2019 International Parkinson and Movement Disorder Society

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Section: Galactosylceramidase (Galc)mentioning

confidence: 99%

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

2019

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“…In several animal models, as well as in patients affected by lysosomal storage disorders, such as GD, GM2 gangliosidosis, Niemann-Pick type C, β-galactosialidosis, NCL10, and Krabbe's disease, α-syn accumulation has been observed. [70][71][72] Moreover, in GD patients, levels of plasma oligomeric α-syn were found higher with respect to controls 73 and negatively associated with leucocyte GCase activity. 74 Increased plasma oligomeric α-syn levels were also found in a small group of patients affected by rarer lysosomal storage disorders, namely Niemann-Pick type C1 and C2 disease, Krabbe's disease, and Wolman's disease.…”

Section: Dysfunction Of the Alp Pathway Leads To Aggregation And Propmentioning

confidence: 88%

“…GALC catalyzes the hydrolysis of different substrates (i.e., galactosylceramide and galactosylsphingosine). Galactosylsphingosine levels were higher in the cerebral cortex of PD patients compared to age‐matched controls . Furthermore, in vitro experiments have shown that galactosylsphingosine accelerates aggregation of α‐syn in a dose‐dependent manner …”

Section: The Issue Of Alp Alterations In Sporadic Pdmentioning

confidence: 97%

“…In several animal models, as well as in patients affected by lysosomal storage disorders, such as GD, GM2 gangliosidosis, Niemann‐Pick type C, β‐galactosialidosis, NCL10, and Krabbe's disease, α‐syn accumulation has been observed . Moreover, in GD patients, levels of plasma oligomeric α‐syn were found higher with respect to controls and negatively associated with leucocyte GCase activity .…”

Section: The Issue Of Alp Alterations In Sporadic Pdmentioning

confidence: 99%

“…Galactosylsphingosine levels were higher in the cerebral cortex of PD patients compared to age-matched controls. 71 Furthermore, in vitro experiments have shown that galactosylsphingosine accelerates aggregation of α-syn in a dose-dependent manner. 108 Thus, in PD, low activity of GCase, aSMase, and GALC, by decreasing Cer levels, may cause a mild reduction of CTSD activity.…”

Section: Dysfunction Of the Alp Pathway Leads To Aggregation And Propmentioning

confidence: 99%

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

et al. 2019

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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

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Insights into Lewy body disease from rare neurometabolic disorders

Erskine

Attems

2021

J Neural Transm

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Professor Kurt Jellinger is well known for his seminal work on the neuropathology of age-associated neurodegenerative disorders, particularly Lewy body diseases. However, it is less well known that he also contributed important insights into the neuropathological features of several paediatric neurometabolic diseases, including Alpers–Huttenlocher syndrome, a syndrome of mitochondrial disease caused by POLG mutations, and infantile neuroaxonal dystrophy, a phenotype resulting from PLA2G6 mutations. Despite these rare diseases occurring in early life, they share many important pathological overlaps with age-associated Lewy body disease, particularly dysregulation of α-synuclein. In this review, we describe several neurometabolic diseases linked to Lewy body disease mechanisms, and discuss the wider context to pathological overlaps between neurometabolic and Lewy body diseases. In particular, we will focus on how understanding disease mechanisms in neurometabolic disorders with dysregulated α-synuclein may generate insights into predisposing factors for α-synuclein aggregation in idiopathic Lewy body diseases.

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Analysis of age-related changes in psychosine metabolism in the human brain

Cited by 23 publications

References 42 publications

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

Emerging links between pediatric lysosomal storage diseases and adult parkinsonism

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

Insights into Lewy body disease from rare neurometabolic disorders

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