Kunath et al., propose that Parkinson’s patients with PARKIN mutations may benefit most from a cell replacement therapy because (i) they often lack synucleinopathy, and (ii) their neurodegeneration is often confined to the nigrostriatal pathway. While patients with PARKIN mutations exhibit clinical signs of Parkinson’s, post-mortem studies to date indicate the majority lack Lewy bodies suggesting the nigral dopaminergic neurons are lost in a cell autonomous manner independent of α-synuclein mechanisms. Furthermore, these patients are usually younger, slow-progressing, and typically do not suffer from complex non-nigral symptoms that are unlikely to be ameliorated by a cell replacement therapy. Transplantation of dopaminergic cells into the putamen of these patients will provide neurons with wild-type PARKIN expression to re-innervate the striatum. The focal nature of PARKIN-mediated neurodegeneration and lack of active synucleinopathy in most young-onset cases makes these patients ideal candidates for a dopaminergic cell replacement therapy. Strategies to improve the outcome of cell replacement therapies for sporadic Parkinson’s include the use of adjunct therapeutics that target α-synuclein spreading and the use of genetically engineered grafts that are resistant to synucleinopathy 14).
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Kunath T, Natalwala A, Chan C, Chen Y, Stecher B, Taylor M, Khan S, Muqit MMK. Are PARKIN patients ideal candidates for dopaminergic cell replacement therapies? Eur J Neurosci. 2018 Dec 26. doi: 10.1111/ejn.14314. [Epub ahead of print] PubMed PMID: 30586214.