TY - JOUR
T1 - A New Synuclein-Transgenic Mouse Model for Early Parkinson’s Reveals Molecular Features of Preclinical Disease
AU - Hendrickx, Diana M.
AU - Garcia, Pierre
AU - Ashrafi, Amer
AU - Sciortino, Alessia
AU - Schmit, Kristopher J.
AU - Kollmus, Heike
AU - Nicot, Nathalie
AU - Kaoma, Tony
AU - Vallar, Laurent
AU - Buttini, Manuel
AU - Glaab, Enrico
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
KW - Disease-stage
KW - Network analysis
KW - Parkinson’s disease
KW - Pathway analysis
KW - Transgenic mouse model
KW - α-Synuclein
UR - http://www.scopus.com/inward/record.url?scp=85091766358&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85091766358&partnerID=8YFLogxK
U2 - 10.1007/s12035-020-02085-z
DO - 10.1007/s12035-020-02085-z
M3 - Article
C2 - 32997293
AN - SCOPUS:85091766358
SN - 0893-7648
VL - 58
SP - 576
EP - 602
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 2
ER -