Abstract
Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, GBA1. In the majority of cases, GD has a non-neuropathic chronic form with adult onset (GD1), while other cases are more acute and severer neuropathic forms with early onset (GD2/3). Currently, no radical therapies are established for GD2/3. Notably, GD1, but not GD2/3, is associated with increased risk of Parkinson’s disease (PD), the elucidation of which might provide a clue for novel therapeutic strategies. In this context, the objective of the present study is to discuss that the evolvability of α-synuclein (αS) might be differentially involved in GD subtypes. Hypothetically, aging-associated PD features with accumulation of αS, and the autophagy-lysosomal dysfunction might be an antagonistic pleiotropy phenomenon derived from αS evolvability in the development in GD1, without which neuropathies like GD2/3 might be manifested due to the autophagy-lysosomal dysfunction. Supposing that the increased severity of GD2/3 might be attributed to the decreased activity of αS evolvability, suppressing the expression of β-synuclein (βS), a potential buffer against αS evolvability, might be therapeutically efficient. Of interest, a similar view might be applicable to Niemann-Pick type C (NPC), another LSD, given that the adult type of NPC, which is comorbid with Alzheimer’s disease, exhibits milder medical symptoms compared with those of infantile NPC. Thus, it is predicted that the evolvability of amyloid β and tau, might be beneficial for the adult type of NPC. Collectively, a better understanding of amyloidogenic evolvability in the pathogenesis of LSD may inform rational therapy development.
Highlights
Gaucher disease (GD) is the most common lysosomal storage disorder (LSD) [1].Due to autosomal recessive mutations of glucocerebrosidase gene 1 (GBA1) encoding the lysosomal hydrolase that is responsible for the degradation of glucosylceramide (GlcCer), GlcCer accumulates intracellularly, leading to a form of sphingolipidosis [1]
Based on previous studies describing that GD1 is a major risk factor of sporadic Parkinson’s disease (PD), it is generally thought that GD1 might be situated upstream of the pathogenesis of PD
It is predicted that the comorbidity of GD1 with PD might be attributed to the increased level of αS evolvability in development/reproduction
Summary
Gaucher disease (GD) is the most common lysosomal storage disorder (LSD) [1]. Due to autosomal recessive mutations of glucocerebrosidase gene 1 (GBA1) encoding the lysosomal hydrolase that is responsible for the degradation of glucosylceramide (GlcCer), GlcCer accumulates intracellularly, leading to a form of sphingolipidosis [1]. While GD3 is a chronic neuronopathic form that exhibits systemic involvement of varying degree with at least one neurological manifestation This group develops the disease somewhat later, but most patients die before their 30th birthday [4]. But most patients diemight beforeaccount their 30th [4] To molecular such a prediction might be the case, increasing αS evolvability through a decrease in mechanisms underlying the different subtypes of GD are unclear. Neurodegenerative diseases such as PD such as PD that are associated with autophagy-lysosomal dysfunction might be manifested as an antagonistic pleiotropy that are associated autophagy-lysosomal dysfunction might be manifested as an antagonistic mechanism mechanism in aging.with (d) Schematics of the differential role of αS evolvability in subtypes of GD.
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