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  • br Transparency document br Introduction

    2019-07-06


    Transparency document
    Introduction Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting around 1–3% of the elderly population over 65 years. The loss of dopaminergic neurons in the susbstantia nigra (SN) pars compacta and Lewy body (LB) inclusions are the main pathological hallmarks of PD. Currently, it is known that PD patients can present non-motor symptoms (olfactory dysfunction, dementia, cognitive decline) prior to developing the characteristic motor symptoms, rigidity, resting tremor and bradykinesia [1]. Most PD cases are sporadic but a number of genetic and environmental risk factors have been identified. Furthermore, mutations in more than 20 genes have been shown to cause autosomal KRN7000 or recessive forms of PD [2]. Amongst these, autosomal dominant mutations in alpha-synuclein (α-syn), leucine-rich repeat kinase 2 (LRRK2), and recessive mutations in the mitochondria-associated proteins PTEN-induced putative kinase 1 (PINK1), Parkin and DJ-1 are amongst the most common (Fig. 1). Here, we briefly review how these proteins control neuronal and mitochondrial function, and discuss how PTMs of these proteins control their behavior, focusing on phosphorylation, SUMOylation and ubiquitination.
    The PD-associated proteins, alpha-synuclein, PINK1, Parkin and DJ-1 α-Syn is a soluble protein highly expressed presynaptically in neurons and can be found as an α-helical structure associated with phospholipids or in an unfolded conformation in the cytosol [3,4]. Misfolded α-syn forms oligomers and fibrils that are highly toxic to cells, and is the main component of Lewy Bodies, intracellular inclusions characteristic of PD which may promote neuroprotection through sequestration of toxic α-syn fibrils, or directly contribute to neurotoxicity [4]. Although its physiological function remains not well understood, α-syn has been strongly implicated in synaptic plasticity and neurotransmitter release [5]. Mutations in α-syn were the first identified genetic cause of PD and subsequently a number of missense mutations, as well as gene duplications, have been observed in PD patients [2]. Mitochondria undergo constant rounds of fission (mitochondrial division), or fusion. These processes, termed mitochondrial dynamics, allow the cell to adapt to fluctuating energy demands, as well as maintaining mitochondrial quality through partitioning damaged mitochondria for subsequent degradation by mitophagy [6]. A large body of evidence implicates mitochondrial dysfunction in PD, and alterations in the balance between mitochondrial fusion and fission, and defects in mitochondrial quality control, are observed in both human patients and animal and cell culture models [6,7]. At the molecular level, mitochondrial fusion and fission are controlled by distinct GTPases – Mfn1 and 2 and OPA1 for fusion, and Drp1 for fission [8]. The balance of activity of these GTPases ultimately determines the balance between fission and fusion, and the morphology of the mitochondrial network. For example, under stress conditions, an imbalance in mitochondrial Drp1 leads to apoptosis [9], and in sporadic PD, aberrant mitochondrial dynamics and the consequent cellular dysfunction have been attributed to Drp1-dependent mitochondrial fragmentation [10,11]. Thus, factors that control the localization and activity of Drp-1 are highly relevant to the pathology of PD. Both PINK1 and Parkin are required in order to maintain mitochondrial quality control. PINK1 is a Ser-Thr kinase with a mitochondrial targeting sequence. In healthy conditions, PINK1 is imported to mitochondria, cleaved and degraded. When there is mitochondrial damage, it accumulates on the cytosolic face of the outer membrane and initiates a quality control pathway involving Parkin [6]. Parkin is a cytosolic E3 ubiquitin ligase recruited to damaged mitochondria by PINK1. PINK1 activates Parkin directly via phosphorylation and indirectly through phosphorylation of ubiquitin, leading to maximal Parkin E3 ligase activity [12]. Parkin can also be found in synaptic vesicles and LB inclusions [10,13], facilitating autophagic degradation of intracellular protein aggregates (aggrephagy) [14]. Nonetheless, it is most well characterized for its role in ubiquitinating mitochondrial target proteins, either to restore mitochondrial proteostasis by targeting misfolded proteins for degradation, or to target the whole organelle for removal by mitophagy. Importantly, amongst the identified targets for Parkin-mediated ubiquitination, are the fusion GTPases Mfn1 and 2 [15] and the fission GTPase Drp1 [8] highlighting Parkin as a central determinant of mitochondrial morphology and quality control.