Transmissible α-synuclein seeding activity in brain and stomach of patients with Parkinson’s disease

Abstract

Cerebral deposition of abnormally aggregated α-synuclein (αSyn) is a neuropathological hallmark of Parkinson’s disease (PD). PD-associated αSyn (αSynPD) aggregates can act as proteinaceous nuclei (“seeds”) able of self-templated propagation. Since this is strikingly reminiscent to properties of proteinaceous infectious particles (prions), lessons learned from prion diseases suggest to test whether transferred αSynPD can propagate and induce neurological impairments or disease in a new host. Two studies that addressed this question provided divergent results. Intracerebral (i.c.) injection of Lewy body extracts from PD patients caused cerebral αSyn pathology, as well as nigrostriatal neurodegeneration, of wild-type mice and macaques, with the mice also showing motor impairments (Recasens et al. 2014, Ann Neurol 75:351–362). In contrast, i.c. transmission of homogenates from PD brains did not stimulate, after “> 360” days post-injection (dpi), pathological αSyn conversion or clinical symptoms in transgenic TgM83+/− mice hemizygously expressing mutated (A53T) human αSyn (Prusiner et al. 2015, PNAS 112:E5308–E5317). To advance the assessment of possible αSynPD hazards by providing further data, we examined neuropathological and clinical effects upon i.c. transmission of brain, stomach wall and muscle tissue as well as blood from PD patients in TgM83+/− mice up to 612 dpi. This revealed a subtle, yet distinctive stimulation of localized αSyn aggregation in the somatodendritic compartment and dystrophic neurites of individual or focally clustered cerebral neurons after challenge with brain and stomach wall homogenates. No such effect was observed with transmitted blood or homogenized muscle tissue. The detected stimulation of αSyn aggregation was not accompanied by apparent motor impairments or overt neurological disease in TgM83+/− mice. Our study substantiated that transmitted αSynPD seeds, including those from the stomach wall, are able to propagate in new mammalian hosts. The consequences of such propagation and potential safeguards need to be further investigated.

The Neural Gut–Brain Axis of Pathological Protein Aggregation in Parkinson’s Disease and Its Counterpart in Peroral Prion Infections

“…This would possibly also help to settle the controversy on reports claiming the detection of pathological αSyn PD deposits in colonic and other gastro-intestinal biopsies years before the onset of PD motor symptoms [ 27 ]. That detection of αSyn PD seeding activity by RT-QuIC assay in GI tissue from the stomach or colon of PD patients is feasible has been recently demonstrated in two independent studies [ 99 , 115 ]. Thus, using the relatively new and powerful analytical tools of RT-QuIC or PMCA for the quantitative detection of αSyn PD -associated seeding activity in human postmortem tissues and bioptic samples may open new perspectives on both the neural gut–brain axis of pathological protein aggregation and the ultrasensitive diagnostic detection of αSyn PD seeds in PD.…”

“…Whether this will be possible in the future is a fundamental question not only because of the lack of accurate animal PD models already mentioned above. To date, stimulation of LP by injected αSyn PD -containing inoculums has only been observed in one animal study (in the form of LN) [ 99 ]. Otherwise, either only the induction of diffuse pathological αSyn accumulations containing phosphorylated αSyn species [ 98 , 100 ] or no αSyn pathology at all [ 101 ] have been detected in the brain of recipient animals after enteric or intracerebral injection of such test materials.…”

Recent Advances in Our Molecular and Mechanistic Understanding of Misfolded Cellular Proteins in Alzheimer’s Disease (AD) and Prion Disease (PrD)

“…Interestingly, dominant tau mutations cause both increased tau aggregation, neuro-inflammation and neurodegeneration, and the pathogenesis of different tauopathies appears to involve pathological tau conformations that serve as templates that recruit native tau proteins to form additional abnormally folded tau proteins that support the further generation of self-aggregating assemblies. These molecular mechanisms are extraordinarily similar to those involving the generation, propagation, diffusion and spreading of prions, and have implications for the potential ‘seeding’ and horizontal transmission of the entire spectrum of human misfolded tau- and α-synuclein-linked diseases, which include AD and Parkinson’s disease (PD) [ 12 , 34 , 36 ].…”

New Inroads Into Our Understanding of the Tauopathies, Alzheimer's Disease, and the Contribution of Altered Protein Conformation to Human Neurological Disease

“…Interestingly, dominant tau mutations cause both increased tau aggregation, neuro-inflammation and neurodegeneration, and the pathogenesis of different tauopathies appear to involve pathological tau conformations that serve as templates that recruit native tau proteins to form abnormally folded tau proteins that support the generation of self-aggregating assemblies. These pathogenic molecular mechanisms: (i) may be augmented by other neurotoxic pathological factors that alter polypeptide conformation and promote protein misfolding; (ii) are extraordinarily similar to those involving the generation, propagation, diffusion, and spreading of prions; and (iii) have implications for the potential "seeding" and horizontal transmission of the entire spectrum of human misfolded tau-, αsynuclein-and amyloid-beta (Aβ) peptide-linked diseases that include AD, PSP and PD (Jaunmuktane and Brandner, 2020;Carlson and Prusiner, 2021;Thomzig et al, 2021).…”

“…This systemic classification has already proved particularly useful in expanding our understanding of both the diversity in the clinical onset and presentation of tau-associated disease and the close molecular and structural interrelationships amongst different human tauopathies. One major challenge is to now develop analytical methodologies to accurately categorize patients according to the molecular structure of the underlying pathological tau protein assemblies to achieve more accurate diagnosis, prognosis, and effective clinical therapies for the wide spectrum of brain diseases involving misfolded tau and other neuronal-enriched fibrillar proteins such as α-synuclein (Carlson and Prusiner, 2021;Thomzig et al, 2021). These cryo-EM-based observations of misfolded tau proteins are also supportive of the prion hypothesis, which predicts that abnormal folding of endogenous natural protein structures into unusual pathogenic isoforms may over time contribute to and/or induce the atypical folding of other similar brain-abundant pathological proteins, while underscoring the age-related and progressive nature of these invariably fatal neurological disorders.…”