Therapeutic Potential of αS Evolvability for NeuropathicGaucher Disease

• Main Authors: Jianshe Wei, Yoshiki Takamatsu, Ryoko Wada, Masayo Fujita, Gilbert Ho, Eliezer Masliah, Makoto Hashimoto
• Format: Article
• Language: English
• Published: MDPI AG 2021-02-01
• Series: Biomolecules
• Subjects: Gaucher disease (GD), Parkinson’s disease (PD), autosomal recessive; α-synuclein (αS), evolvability; antagonistic pleiotropy; β-synuclein (βS)
• Online Access: https://www.mdpi.com/2218-273X/11/2/289

Gaucher disease (GD), the most common lysosomal storage disorder (LSD), is caused by autosomal recessive mutations of the glucocerebrosidase gene, <i>GBA1</i>. 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)<i>, the </i>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.