Therapeutic Potential of α-Synuclein Evolvability for Autosomal Recessive Parkinson’s Disease

Figure 4

Illustration of the evolvability-based therapeutic strategy against autosomal recessive PD. The majority of PD is late-onset sPD associated with aggregation of a wild type αS. sPD might be caused by interaction of various genes, including SNCA, LRRK2, MAPT, and GBA, with environmental factors, such as trauma, pesticide, and hypoxia. In the reproductive stage, αS evolvability is beneficial for various cellular functions, such as mitochondria, lysosome-autophagy, and ubiquitin-proteasome system. However, these functions are later impaired through antagonistic pleiotropy, and the late-onset PD is manifested in aging. AD-PD is caused by missense mutations of the AD-PD genes, including SNCA (PARK 1 and 4), LRRK2 (PARK 8), VPS35 (PARK 17), and CHCHD2 (PARK 21) in addition to SNCB (V70 M and P123H). The neuropathology in AD-PD is similar to that of sPD and is characterized by aggregation of αS. On the other hand, AR-PD caused by missense mutations of the AD-PD genes, including Parkin (PARK 2), DJ-1 (PARK 6), PINK1 (PARK 7), ATP13A2 (PARK 9), PLA2G6 (PARK 14), FOXO7 (PARK 15), and DNAJC16 (PARK 19), and is associated with impairment of ubiqutin-proteasome, mitochondria, and autophagy, namely, mitophagy in the early-onset PD. Given the buffering effect of βS on αS evolvability, increase in αS evolvability through βS downregulation might be therapeutically beneficial in autosomal recessive PD. To achieve this, βS expression could be reduced by various methods, including ASO targeting βS mRNA and passive βS immunization therapy (Tx).