The crucial role of VPS35 and SHH in Parkinson's disease: Understanding the mechanisms behind the neurodegenerative disorder.

Parkinson's disease (PD) is indeed a complex neurodegenerative disorder recognized by the progressive depletion of dopaminergic neurons in the brain, particularly in the substantia nigra region, leading to motor impairments and other symptoms. But at the molecular level, the study about PD still lacks. As the number of cases worldwide continues to increase, it is critical to focus on the cellular and molecular mechanisms of the disease's presentation and neurodegeneration to develop novel therapeutic approaches. At the molecular level, the complexity is more due to the involvement of vacuolar protein sorting 35 (VPS35) and sonic hedgehog (SHH) signaling in PD (directly or indirectly), leading to one of the most prominent hallmarks of the disease, which is an accumulation of α-synuclein. This elevated pathogenesis may result from impaired autophagy due to mutation in the case of VPS35 and impairment in SHH signaling at the molecular level. The traditional understanding of PD is marked by the disruption of dopaminergic neurons and dopaminergic signaling, which exacerbates symptoms of motor function deficits. However, the changes at the molecular level that are being disregarded also impact the overall health of the dopaminergic system. Gaining insight into these two unique mechanisms is essential to determine whether they give neuroprotection or have no effect on the health of neurons. Hence, here we tried to simplify the understanding of the role of VPS35 and SHH signaling to comprehend it in one direction.