Molecular Features of Parkinson's Disease in Patient‐Derived Midbrain Dopaminergic Neurons

Abstract

A BS TRACT: Background: Despite intense efforts to develop an objective diagnostic test for Parkinson's disease, there is still no consensus on biomarkers that can accurately diagnose the disease. Objective: Identification of biomarkers for idiopathic Parkinson's disease (PD) may enable accurate diagnosis of the disease. We tried to find molecular and cellular differences in dopaminergic (DA) neurons derived from healthy subjects and idiopathic PD patients with or without rest tremor at onset. Methods: We measured the expression of genes controlling dopamine synthesis, sequestration, and catabolism as well as the levels of corresponding metabolites and reactive oxygen species in midbrain DA neurons differentiated from induced pluripotent stem cells (iPSCs) of healthy subjects and PD patients with or without rest tremor.Results: Significant differences in DA-related gene expression, metabolites, and oxidative stress were found between midbrain DA neurons derived from healthy subjects and patients with PD. DA neurons derived from PD patients with or without rest tremor at onset exhibited significant differences in the levels of some of these transcripts, metabolites, and oxidative stress. Conclusion:The unique combination of these quantifiable molecular and cellular traits in iPSC-derived midbrain DA neurons can distinguish healthy subjects from idiopathic PD patients and segregate PD patients with or without rest tremor at onset. The strategy may be used to develop an objective diagnostic test for PD.

Hubungan Antara Pola Makan dan Aktivitas Fisik Terhadap Tingkat Depresi di Masa Pandemi Pada Pelajar SMAN 1 Manyar Gresik, Indonesia

“…Brain neurotransmitters are formed from amino acids. Dopamine is made of tyrosine, and serotonin is made from tryptophan 108,109 . Dopamine plays a vital role in the brain, precisely in the mesolimbic dopaminergic pathway.…”

Aging, Parkinson’s Disease, and Models: What Are the Challenges?

“…These reprogrammed and differentiated DA neurons recapitulate many of the cellular mechanisms associated with PD, including mitochondrial dysfunction, lysosomal abnormalities, α-synuclein pathology (particularly increased levels of phospho-α-synuclein), and susceptibility to α-synuclein preformed fibril (PFF) seeding 42 – 47 . In addition, for the proportion of neurons that successfully differentiate from iPSCs, markers of apoptosis and neuron viability differ between PD and healthy control donors 48 , 49 , indicating PD patient-derived neurons are more susceptible to cell death during differentiation. This preferential neuron cell during differentiation could be viewed as strength as it recapitulates the neuron death observed in PD patients; however, those neurons that are lost during differentiation could be in fact those neurons that need to be studied to understand the neuronal death pathways active in PD.…”

“…Hence, further studies investigating that population of vulnerable cells throughout differentiation would be warranted. Furthermore, DA, DA metabolites, and expression of genes controlling DA synthesis and sequestration (DOPAC and homovanillic acid) differ even between PD patients displaying varying severity of disease 49 . These changes in DA metabolites and neuronal complexity are similar to those reported from several in vivo rodent models of PD (discussed below).…”

Mitochondrial dysfunction of induced pluripotent stem cells-based neurodegenerative disease modeling and therapeutic strategy

“…In PD iPSC-derived DA neurons, Jian Feng found higher protein level of tyrosine hydroxylase (TH) and high ROS levels. Moreover, there is no significant alterations in DA levels, which might be due to homeostatic regulation ( Ren et al, 2022 ). However, decreased TH mRNA level and DA release were reported in postmortem brain tissues and cerebrospinal fluid of PD patients respectively ( Goldstein et al, 2012 ; Zhang et al, 2022 ).…”