Abstract
The lysosome is a central player in the cell, acting as a clearing house for macromolecular degradation, but also plays a critical role in a variety of additional metabolic and regulatory processes. The lysosome has recently attracted the attention of neurobiologists and neurologists since a number of neurological diseases involve a lysosomal component. Among these is Parkinson’s disease (PD). While heterozygous and homozygous mutations in GBA1 are the highest genetic risk factor for PD, studies performed over the past decade have suggested that lysosomal loss of function is likely involved in PD pathology, since a significant percent of PD patients have a mutation in one or more genes that cause a lysosomal storage disease (LSD). Although the mechanistic connection between the lysosome and PD remains somewhat enigmatic, significant evidence is accumulating that lysosomal dysfunction plays a central role in PD pathophysiology. Thus, lysosomal dysfunction, resulting from mutations in lysosomal genes, may enhance the accumulation of α-synuclein in the brain, which may result in the earlier development of PD.
Highlights
The lysosome is a membrane-bound organelle first described by Christian de Duve in the 1950s [1,2]
Significant advances in delineating the relationship between mutations in the SMPD1 gene, which causes Niemann–Pick disease types A and B [27], and Parkinson’s disease (PD) have been reported in the past few years, with SMPD1 repeatedly identified as a genetic risk factor for PD [28,29]
The majority of clinical studies on the relationship between PD and lysosomal storage disease (LSD) were performed on carriers rather than LSD patients, due to the low individual prevalence of LSDs and their early age of death
Summary
The lysosome is a membrane-bound organelle first described by Christian de Duve in the 1950s [1,2]. The Human Lysosome Gene Database contains about 400 lysosomal proteins (http://lysosome.unipg.it) [11] and a recent proteomics study suggested 343 unique lysosomal proteins [12] These numbers are significantly more than the roughly 50 proteins currently known to be associated with an LSD, and that were analyzed in the whole exome sequencing study [10]. Might some of these other lysosomal genes be associated with LSDs, even though not all of the approximately 400 proteins in this database are likely to be bonafide lysosomal proteins?. We update studies performed in the last decade or so that lend further support to the association between the lysosome and PD, and briefly discuss progress on understanding the mechanistic relationship between the lysosome and PD
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