Interlinked role of ASN, TDP-43 and Miro1 with parkinopathy: Focus on targeted approach against neuropathy in parkinsonism.

Abstract

Parkinsonism is a complex neurodegenerative disease that is difficult to differentiate because of its idiopathic and unknown origins. The hereditary parkinsonism known as autosomal recessive-juvenile parkinsonism (AR-JP) is marked by tremors, dyskinesias, dystonic characteristics, and manifestations that improve sleep but do not include dementia. This was caused by deletions and point mutations in PARK2 (chromosome 6q25.2-27). Diminished or unusual sensations (paresthesias), loss of neuron strength both in the CNS and peripheral nerves, and lack of motor coordination are the hallmarks of neuropathy in parkinsonism. The incidence of parkinsonism during oxidative stress and ageing is associated with parkinopathy. Parkinopathy is hypothesized to be triggered by mutation of the parkin (PRKN) gene and loss of normal physiological functions of PRKN proteins, which triggers their pathogenic aggregation due to conformational changes. Two important genes that control mitochondrial health are PRKN and phosphatase and tensin homologue deleted on chromosome 10-induced putative kinase 1 (PINK1). Overexpression of TAR DNA-binding protein-43 (TDP-43) increases the aggregation of insoluble PRKN proteins in OMM. Foreign α-synuclein (ASN)promotes parkinopathy via S-nitrosylation and hence has a neurotoxic effect on dopaminergic nerves. Miro1(Miro GTPase1), a member of the RAS superfamily, is expressed in nerve cells. Due to PINK1/PRKN and Miro1's functional relationship, an excess of mitochondrial calcium culminates in the destruction of dopaminergic neurons. An interlinked understanding of TDP-43, PINK1/PRKN, ASN, and Miro1 signalling in the communication among astrocytes, microglia, neurons, and immune cells within the brain explored the pathway of neuronal death and shed light on novel strategies for the diagnosis and treatment of parkinsonism.