Defects in trafficking bridge Parkinson's disease pathology and genetics

Abstract

Parkinson's disease is a debilitating, age-associated movement disorder. A central aspect of the pathophysiology of Parkinson's disease is the progressive demise of midbrain dopamine neurons and their axonal projections, but the underlying causes of this loss are unclear. Advances in genetics and experimental model systems have illuminated an important role for defects in intracellular transport pathways to lysosomes. The accumulation of altered proteins and damaged mitochondria, particularly at axon terminals, ultimately might overwhelm the capacity of intracellular disposal mechanisms. Cell-extrinsic mechanisms, including inflammation and prion-like spreading, are proposed to have both protective and deleterious functions in Parkinson's disease.

Membrane Trafficking Illuminates a Path to Parkinson’s Disease

“…including oxidative stress (Hasegawa et al 2003(Hasegawa et al , 2007Hasegawa 2010), endoplasmic reticulum stress (Sugeno et al 2008;Mercado et al 2016), mitochondrial dysfunction (Mizuno et al 1998;Rothfuss et al 2009), misfolded protein toxicity Takeda et al 2006), ubiquitin-proteasome dysfunction Vilchez et al 2014;Matsuda 2016), neuroinflammation , impairment of the autophagy-lysosome system (Ferrucci et al 2008;Oshima et al 2016), and alterations in the membrane trafficking pathway (Abeliovich and Gitler 2016). Among them, recent advances in clinical genetics and studies using model organisms have emphasized that the membrane trafficking pathway contributes immensely to the pathogenesis of PD and related neurodegenerative disorders.…”

Heterogeneous clinical spectrum of DNAJC12-deficient hyperphenylalaninemia: from attention deficit to severe dystonia and intellectual disability

“…The finding of DNAJC12-deficient patients presenting with HPA and abnormal brain catecholamines has identified the PAH enzyme but also tyrosine and tryptophan hydroxylases as interacting ‘client’ proteins (see also discussion in ref 7). In this context, it is interesting to note that ectopic expression of the HSP40/HSP70 complex was reported to rescue GTPCH activity of the GCH1 variant p.Gly201Glu that was found in a Dopa-responsive dystonia patient10 and that DNAJC6 and DNAJC13 were associated with, respectively, autosomal recessive and dominant juvenile Parkinsonism11 12 (for an overview on defects in trafficking and Parkinson’s disease, see ref 13). A more detailed physiological analysis is obviously required to fully understand these various interactions and interdependences.…”

VPS35-Linked Parkinson’s Disease Resembles the Idiopathic Disease: A Review of Clinical Trials

“…While within the last half decade we considerably learned about the genetics of VPS35 patients, we have nothing at hand to offer our clinical VPS35 patients. More human case reports including neuropathology would be needed to find a specific clinical marker of VPS35 patients to allow a targeted referral to genetic testing [22][23][24][25][26].…”