Resilience, Dysregulation, and Rescue of Basal Ganglia Indirect Pathway Function in Progressive Parkinsonism

Project Summary
While the bradykinetic and akinetic symptoms of Parkinson’s disease (PD) are clearly linked to the degeneration
of substantia nigra dopaminergic (SN DAergic) neurons1-3, the mechanisms that underlie the emergence and
escalation of basal ganglia circuit and motor dysfunction remain poorly defined. Degeneration of SN DAergic
neurons long precedes the expression of symptoms in PD4-6. At the point of diagnosis ~50-75% of nigrostriatal
DAergic axons and ~30% of SN DAergic neurons no longer express DA cell markers or have been lost7,8, arguing
for an extensive prodromal period, masked by compensatory mechanisms9-25. As degeneration proceeds,
increasingly dysregulated activity24,26-41 and maladaptive plasticity13-24 within the indirect pathway may
progressively degrade basal ganglia computation, leading to motor deficits17,18,26-28,36-40. This circuit
pathophysiology has also been suggested as an additional source of bioenergetic stress in SN DAergic neurons
that could accelerate their degeneration42-47. Although plausible, these concepts cannot be rigorously studied in
acute toxin models that mimic the absence of DA in advanced PD but not the spatiotemporal pattern of DAergic
neuron degeneration in patients48,49. To fill this gap, we propose to examine the emergence of parkinsonism and
its impact of indirect pathway function in the MitoPark model of PD50. MitoPark mice are generated through
genetic deletion of the nuclear encoded mitochondrial transcription factor TFAM in DAergic neurons, which
causes mitochondrial dysfunction50-52, a consistent vulnerability of these cells in familial and sporadic forms of
PD53-58. These mice recapitulate key aspects of PD, including: 1) progressive SN DAergic neuron degeneration
and levodopa-sensitive motor deficits, but within a compressed, experimentally tractable time frame spanning 6-
7 months50,51,59; 2) relative susceptibility of SN DAergic neuron axon terminals in the dorsal striatum in the initial
stages of parkinsonism50,52,59-61; 3) relative susceptibility of SN versus ventral tegmental area DAergic
neurons50,51,59; 4) circuit plasticity and pathophysiology analogous to that in advanced PD and its models (pilot
data). Using in vivo and ex vivo electrophysiological, optogenetic, chemogenetic, 2-photon imaging,
electrochemical, immunohistochemical, and behavioral approaches, we propose 3 specific aims: 1) determine
the mechanisms responsible for the retention of indirect pathway and motor function in prodromal MitoPark mice;
2) determine the mechanisms underlying progressive indirect pathway and motor dysfunction in symptomatic
MitoPark mice; 3) determine whether motor dysfunction and degeneration of SN DAergic neurons can be
rescued in symptomatic MitoPark mice by chemogenetically manipulating indirect pathway activity. Through the
execution of this research, we will learn why aspects of basal ganglia indirect pathway function are initially
resilient to but ultimately dysregulated by degeneration of SN DAergic neurons, and whether chemogenetic
indirect pathway manipulation is an effective symptomatic and/or disease-modifying therapy for parkinsonism.

Grant Number: 5R01NS041280-25
NIH Institute/Center: NIH
Principal Investigator: Mark Bevan