Disease–modifying therapies in Parkinson's disease

Abstract

Parkinson disease (PD) is a progressive neurodegenerative disorder. Neuropathological hallmarks of PD are prominent loss of dopaminergic (DA) neurons in the substantia nigra and formation of intraneuronal protein inclusions termed Lewy bodies, composed mainly of α–synuclein (αSyn). PD has serious issues for both patients and clinicians, because this disorder is typically difficult to treat with traditional pharmacological approaches once develop due to the complexicity of the nervous system and physical barriers that limit distribution of medications into the central nervous system after peripheral administration. Patients of this disorder suffer from both symptoms and sequelae in their remaining lifetime. New strategies are progressively developed to overcome the unmet medical needs in conventional therapy. The recent discovery that αSyn can transmit from cell to cell in a prion–like fashion suggests that the therapy to regulate the expression of αSyn such as antibody, vaccine and antisense oligonucleotide might be viable options for PD treatment. On the other hand, mitochondrial dysregulation, such as reduced complex I activity, bioenergetic failure, and perturbation of mitochondrial dynamics and mitophagy, has long been implicated in the pathogenesis of PD. Recently, we found that necdin promoted mitochondrial biogenesis through stabilization of endogenous PGC–1α to exert neuroprotection against mitochondrial insults. Necdin will also be one of candidates of new treatment to delay the progression of PD. I will introduce these new topics for disease–modifying therapies in PD in this review.