Are PARKIN patients ideal candidates for dopaminergic cell replacement therapies?

Abstract

Parkinson's is a heterogeneous, complex condition. Stratification of Parkinson's subtypes will be essential to identify those that will benefit most from a cell replacement therapy. Foetal mesencephalic grafts can alleviate motor symptoms in some Parkinson's patients. However, on‐going synucleinopathy results in the grafts eventually developing Lewy bodies, and they begin to fail. We propose that Parkinson's patients with PARKIN mutations may benefit most from a cell replacement therapy because (a) they often lack synucleinopathy, and (b) 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.

Parkinson's: A Disease of Aberrant Vesicle Trafficking

“…Consistent with this, patients harboring PINK1 or Parkin mutations exhibit identical phenotypes with early-onset disease, an excellent response to L-Dopa, and a relatively high frequency of dystonia and dyskinesias (Lunati et al 2018). Pathologically, PINK1 and Parkin patient brains exhibit relatively restricted neurodegeneration within the substantia nigra (SN) and a paucity of LBs, although variability in LB burden has been reported in select cases for each gene (Kunath et al 2019).…”

An autopsy case of pure nigropathy with TUBA4A nonsense mutation

“…Previous studies have shown that most familial Parkinson's disease (PD) cases with genetic variants (e.g., Parkin , LRRK2 and PINK1 ) do not have Lewy pathology in the brain, and “pure nigropathy” tends to be used as a pathological diagnosis in such patients[1].…”

Bioengineering a pre-vascularized pouch for subsequent islet transplantation using VEGF-loaded polylactide capsules

“…In addition, cellular transplantation can be theoretically used for the therapy of haemophilia, liver failure, Parkinson's disease, transversal spinal cord injuries and others. [6][7][8][9] Outcomes of these procedures still vary widely but it seems likely that the procedure's effectiveness can be considerably improved via optimization of the transplantation site and the procedure itself. The generally accepted requirement for an adequate environment for an engraftment of transplanted cells inspires many groups to pay great attention to the characterization and subsequent development of the optimal transplantation site.…”