A New Synuclein-Transgenic Mouse Model for Early Parkinson’s Reveals Molecular Features of Preclinical Disease

Abstract

Understanding Parkinson’s disease (PD), in particular in its earliest phases, is important for diagnosis and treatment. However, human brain samples are collected post-mortem, reflecting mainly end-stage disease. Because brain samples of mouse models can be collected at any stage of the disease process, they are useful in investigating PD progression. Here, we compare ventral midbrain transcriptomics profiles from α-synuclein transgenic mice with a progressive, early PD-like striatal neurodegeneration across different ages using pathway, gene set, and network analysis methods. Our study uncovers statistically significant altered genes across ages and between genotypes with known, suspected, or unknown function in PD pathogenesis and key pathways associated with disease progression. Among those are genotype-dependent alterations associated with synaptic plasticity and neurotransmission, as well as mitochondria-related genes and dysregulation of lipid metabolism. Age-dependent changes were among others observed in neuronal and synaptic activity, calcium homeostasis, and membrane receptor signaling pathways, many of which linked to G-protein coupled receptors. Most importantly, most changes occurred before neurodegeneration was detected in this model, which points to a sequence of gene expression events that may be relevant for disease initiation and progression. It is tempting to speculate that molecular changes similar to those changes observed in our model happen in midbrain dopaminergic neurons before they start to degenerate. In other words, we believe we have uncovered molecular changes that accompany the progression from preclinical to early PD.

Proteome profiling of cerebrospinal fluid reveals biomarker candidates for Parkinson’s disease

“… 47 , 48 Our results are in line with previous studies that identified OMD as a potential blood biomarker for PD 49 and upregulated in a SNCA transgenic mouse model. 50 A recent study has also shown the elevated expression of CD44 in the substantia nigra of human PD brains and CD44-mediated anti-inflammatory effects in primary mouse astrocytes. 51 Induced expression of CD44 by α-synuclein in microglia, likely affecting PD pathogenesis by recruiting reactive microglia into the pathological region of the PD brain, was also reported.…”

Apoptosis signal-regulating kinase 1 (Ask1) deficiency alleviates MPP+-induced impairment of evoked dopamine release in the mouse hippocampus

“…Disruption of the dopaminergic system is implicated in neurological diseases such as Parkinson’s disease (PD) and Huntington’s disease. PD involves the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), leading to motor deficits and potentially non-motor disorders like mild cognitive impairment (MCI) and dementia ( Kikuchi et al, 2017 ; Hendrickx et al, 2021 ). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a useful tool to induce the development of both late and early PD models, can reproduce both motor and non-motor symptoms ( Grandi et al, 2018 ).…”

“…In addition to the chronic effects leading to the apoptotic death of dopaminergic neurons in the substantia nigra pars compacta (SNc), these substances can also be used to explore more subtle effects on dopaminergic axons or varicosities. Neuropathological and neurological changes might occur before obvious neurodegeneration, potentially triggered by environmental toxins or genetic factors ( Grandi et al, 2018 ; Hendrickx et al, 2021 ). Therefore, investigating alterations in dopamine release probabilities caused by low concentrations of the neurotoxin MPP + and exploring protective approaches is an important research objective ( Lisman et al, 2017 ).…”