TY - JOUR
T1 - The heterogeneity of Parkinson’s disease
AU - Wüllner, Ullrich
AU - Borghammer, Per
AU - Choe, Chi un
AU - Csoti, Ilona
AU - Falkenburger, Björn
AU - Gasser, Thomas
AU - Lingor, Paul
AU - Riederer, Peter
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6
Y1 - 2023/6
N2 - The heterogeneity of Parkinson’s disease (PD), i.e. the various clinical phenotypes, pathological findings, genetic predispositions and probably also the various implicated pathophysiological pathways pose a major challenge for future research projects and therapeutic trail design. We outline several pathophysiological concepts, pathways and mechanisms, including the presumed roles of α-synuclein misfolding and aggregation, Lewy bodies, oxidative stress, iron and melanin, deficient autophagy processes, insulin and incretin signaling, T-cell autoimmunity, the gut–brain axis and the evidence that microbial (viral) agents may induce molecular hallmarks of neurodegeneration. The hypothesis is discussed, whether PD might indeed be triggered by exogenous (infectious) agents in susceptible individuals upon entry via the olfactory bulb (brain first) or the gut (body-first), which would support the idea that disease mechanisms may change over time. The unresolved heterogeneity of PD may have contributed to the failure of past clinical trials, which attempted to slow the course of PD. We thus conclude that PD patients need personalized therapeutic approaches tailored to specific phenomenological and etiologic subtypes of disease.
AB - The heterogeneity of Parkinson’s disease (PD), i.e. the various clinical phenotypes, pathological findings, genetic predispositions and probably also the various implicated pathophysiological pathways pose a major challenge for future research projects and therapeutic trail design. We outline several pathophysiological concepts, pathways and mechanisms, including the presumed roles of α-synuclein misfolding and aggregation, Lewy bodies, oxidative stress, iron and melanin, deficient autophagy processes, insulin and incretin signaling, T-cell autoimmunity, the gut–brain axis and the evidence that microbial (viral) agents may induce molecular hallmarks of neurodegeneration. The hypothesis is discussed, whether PD might indeed be triggered by exogenous (infectious) agents in susceptible individuals upon entry via the olfactory bulb (brain first) or the gut (body-first), which would support the idea that disease mechanisms may change over time. The unresolved heterogeneity of PD may have contributed to the failure of past clinical trials, which attempted to slow the course of PD. We thus conclude that PD patients need personalized therapeutic approaches tailored to specific phenomenological and etiologic subtypes of disease.
KW - Disease mechanism
KW - Inflammation
KW - Parkinson’s disease
KW - Pathophysiology
KW - Personalized medicine
KW - Phenotypes
UR - http://www.scopus.com/inward/record.url?scp=85159367945&partnerID=8YFLogxK
U2 - 10.1007/s00702-023-02635-4
DO - 10.1007/s00702-023-02635-4
M3 - Review article
C2 - 37169935
AN - SCOPUS:85159367945
SN - 0300-9564
VL - 130
SP - 827
EP - 838
JO - Journal of Neural Transmission
JF - Journal of Neural Transmission
IS - 6
ER -