Growth differentiation factor 5: a neurotrophic factor with neuroprotective potential in Parkinson’s disease

Abstract

Parkinson’s disease is the most common movement disorder worldwide, affecting over 6 million people. It is an age-related disease, occurring in 1% of people over the age of 60, and 3% of the population over 80 years. The disease is characterized by the progressive loss of midbrain dopaminergic neurons from the substantia nigra, and their axons, which innervate the striatum, resulting in the characteristic motor and non-motor symptoms of Parkinson’s disease. This is paralleled by the intracellular accumulation of α-synuclein in several regions of the nervous system. Current therapies are solely symptomatic and do not stop or slow disease progression. One promising disease-modifying strategy to arrest the loss of dopaminergic neurons is the targeted delivery of neurotrophic factors to the substantia nigra or striatum, to protect the remaining dopaminergic neurons of the nigrostriatal pathway. However, clinical trials of two well-established neurotrophic factors, glial cell line-derived neurotrophic factor and neurturin, have failed to meet their primary end-points. This failure is thought to be at least partly due to the downregulation by α-synuclein of Ret, the common co-receptor of glial cell line-derived neurorophic factor and neurturin. Growth/differentiation factor 5 is a member of the bone morphogenetic protein family of neurotrophic factors, that signals through the Ret-independent canonical Smad signaling pathway. Here, we review the evidence for the neurotrophic potential of growth/differentiation factor 5 in in vitro and in vivo models of Parkinson’s disease. We discuss new work on growth/differentiation factor 5’s mechanisms of action, as well as data showing that viral delivery of growth/differentiation factor 5 to the substantia nigra is neuroprotective in the α-synuclein rat model of Parkinson’s disease. These data highlight the potential for growth/differentiation factor 5 as a disease-modifying therapy for Parkinson’s disease.

A Basal Ganglia Model for understanding Working Memory Functions in Healthy and Parkinson’s Conditions

“…However, in this wide range of studies there is a conspicuous paucity of models that address alterations of WM functions under disease conditions such as PD. When it comes to cognitive aspects and WM deficits of PD there are only a few studies (Goulding et al, 2022;Hazy et al, 2007;Schroll & Hamker, 2013), and there is still a huge scope in studying different aspects of WM deficits in detail.…”

“…Experimental data from different cognitive tasks performed by PD patients, under medicated and unmedicated conditions, show specific WM impairments and the reasons for which are still not clearly known, when compared to other modalities like motor, speech, and gait & balance (Cai et al, 2022;Ye et al, 2022). There are only a handful of BG models that incorporate the PD condition in WM tasks; and even they are often not general enough to describe PD-related WM deficits in a variety of WM tasks described in the literature (Goulding et al, 2022;Hazy et al, 2007;Schroll et al, 2012).…”