Journal
FEBS JOURNAL
Volume 285, Issue 19, Pages 3591-3603Publisher
WILEY
DOI: 10.1111/febs.14393
Keywords
-synuclein; autophagy; glucocerebrosidase; Parkinson disease; unfolded protein response
Categories
Funding
- NIHR UCLH-BRC [RCF103/AS/2014]
- Medical Research Council UK [MR/M006646/1]
- Kattan Trust Fund
- MRC [MR/M006646/1] Funding Source: UKRI
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GBA encodes the lysosomal enzyme glucocerebrosidase (GCase), an enzyme involved in sphingolipid metabolism. Mutations in the GBA gene are numerically the most important risk factor for developing Parkinson disease (PD) accounting for at least 5% of all PD cases. Furthermore, loss of GCase activity is found in sporadic PD brains. Lysosomal dysfunction is thought to play a principal role in PD pathogenesis and in particular its effect on the metabolism of -synuclein. A hallmark of PD is the presence of intraneuronal protein inclusions called Lewy bodies, which are composed mainly of -synuclein. Cellular and animal models of GCase deficiency result in lysosomal dysfunction, and in particular the autophagy lysosome pathway, resulting in the accumulation of -synuclein. Some forms of mutant GCase unfold in the endoplasmic reticulum activating the unfolded protein response, which might also contribute to PD pathogenesis. It has also been suggested that accumulation of GCase substrates glucosylceramide/glucosylsphingosine may contribute to GBA-PD pathogenesis. Mitochondrial dysfunction and neuroinflammation are associated with GCase deficiency and have also been implicated in the aetiology of PD. This review discusses these points and highlights potential treatments that might be effective in treating GCase deficiency in PD.
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