Abstract
α-Synuclein aggregation has been linked to Gaucher’s disease (GD) and Krabbe’s disease (KD), lysosomal conditions affecting glycosphingolipid metabolism. α-Synuclein pathology has been directly attributed to the dysregulation of glycosphingolipids in both conditions, specifically to increased galactosylsphingosine (psychosine) content in the context of KD. Furthermore, the gene (GALC) coding for the psychosine degrading enzyme galactosylceramidase (GALC), has recently been identified as a risk loci for Parkinson’s disease. However, it is unknown if changes in psychosine metabolism and GALC activity in the context of the aging human brain correlate with Parkinson’s disease. We investigated psychosine accumulation and GALC activity in the aging brain using fresh frozen post-mortem tissue from Parkinson’s (PD, n = 10), Alzheimer’s (AD, n = 10), and healthy control patients (n = 9), along with tissue from neuropsychiatric patients (schizophrenia, bipolar disorder and depression, n = 15 each). An expanded mutational analysis of PD (n = 20), AD (n = 10), and healthy controls (n = 30) examined if PD was correlated with carriers for severe GALC mutations. Psychosine content within the cerebral cortex of PD patients was elevated above control patients. Within all patients, psychosine displayed a significant (p<0.05) and robust regional distribution in the brain with higher levels in the white matter and substantia nigra. A mutational analysis revealed an increase in the incidence of severe GALC mutations within the PD patient population compared to the cohorts of Alzheimer’s patients and healthy controls tested. In addition to α-synuclein pathology identified in the KD brain, control patients identified as GALC mutational carriers or possessing a GALC pathogenic variant had evidence of α-synuclein pathology, indicating a possible correlation between α-synuclein pathology and dysregulation of psychosine metabolism in the adult brain. Carrier status for GALC mutations and prolonged exposure to increased psychosine could contribute to α-synuclein pathology, supporting psychosine metabolism by galactosylceramidase as a risk factor for Parkinson’s disease.
Highlights
A growing body of evidence underlines the role lysosomal dysfunction contributes to the pathology in several neurological conditions, including demyelination, late-onset neurodegenerative diseases, and aging [1, 2]
We described proteopathic aggregations of fibrillized α-synuclein in central neurons of infantile and young adult patients affected by Krabbe’s disease (KD), a lysosomal sphingolipidosis caused by mutations in the galactosylceramidase (GALC) gene [8], describing for the first time a link between GALC metabolism and synucleinopathies [9]
A neurodegenerative cohort was comprised of agematched patients diagnosed with Parkinson’s disease (PD), Alzheimer’s disease (AD), or as healthy controls, along with tissue from infantile and late-onset KD patients as positive controls of psychosine lipidosis
Summary
A growing body of evidence underlines the role lysosomal dysfunction contributes to the pathology in several neurological conditions, including demyelination, late-onset neurodegenerative diseases, and aging [1, 2]. A robust link has been described between Parkinson’s disease (PD) and Gaucher’s disease [3,4,5], a lysosomal sphingolipidosis caused by mutations in the glucocerebrosidase (GBA1) gene. We described proteopathic aggregations of fibrillized α-synuclein in central neurons of infantile and young adult patients affected by Krabbe’s disease (KD), a lysosomal sphingolipidosis caused by mutations in the galactosylceramidase (GALC) gene [8], describing for the first time a link between GALC metabolism and synucleinopathies [9]. Whether alterations in the psychosine metabolism resulting from inefficient lysosomal function could contribute to α-synuclein pathology in the adult human brain during aging is currently unknown
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