The MCI park model of Professor Surmeier's group highlights the importance of mitochondria and local dopamine release in the development of motor deficits.
A Parkinson's patient bent over forward with mask face and implied tremors (iStock.com/LCOSMO).
More than 20 different genes can trigger Parkinson's disease in their mutated form, some of which encode proteins that are important for the assembly and disassembly of mitochondria. As described in detail in my book on neurodegeneration in chapter 2.1.2, mitochondria are the cellular power plants that produce our most important energy carrier, adenosine triphosphate (ATP), by means of so-called oxidative phosphorylation.
Disturbances in the energy supply of cells lead to premature aging (senescence) and even cell death. The turnover of mitochondria is apparently of decisive importance in the development of Parkinson's symptoms, since the metabolically and bioenergetically highly stressed nerve cells in the brain stem are particularly affected. However, disorders of mitochondrial activities are found not only in genetic but also in sporadic Parkinson's disease.
Mitochondria proliferate by growth and division and are subject to quality control. Their quantity and size are constantly adjusted to the energy requirements of the cell. Electron chain proteins necessary for cellular respiration are located at mitochondrial membranes. A key enzyme of the mitochondrial respiratory chain is NADH dehydrogenase (called complex I or MCI).
Summary of the hazards to which dopaminergic neurons are exposed in the substantia nigra along with their axons, which are highly branched in the target area, the striatum. Automatic depolarization (1) leads to increased calcium influx into the cell, which activates caspases and can damage mitochondria (2). Free radicals formed in mitochondria and by membrane-bound enzymes (3) lead to oxidative stress and are thus potentially toxic. Mostly genetic defects in mito- and autophagy (4) and in the endo-lysosomal system (5) disrupt protein homeostasis and result in axonal degeneration and ultimately neuronal cell death (Fig. 2.10 from Klimaschewski L.P., Aging and neurodegenerative diseases - why are neurons lost? In: Parkinson's and Alzheimer's disease today. Springer, 2021)
In a recent work from the group of James Surmeier from Chicago (Northwestern University), a catalytic subunit of complex I was specifically knocked down in dopaminergic neurons in mice. This subunit is encoded by the NDUFS2 gene. The animals used by Patricia Gonzalez-Rodriguez and colleagues represent the first animal model of the disease in which complex I has been effectively knocked out. The animals survive because only a subpopulation of neurons in the brainstem is affected, namely those that produce the dopamine transporter.
The motor deficits in Parkinson's disease are attributed to the failure of dopaminergic neurons in the substantia nigra of the midbrain. In NDUFS2-deficient mice, neuronal degeneration is found right here. However, since there are people with mutations in the NDUFS2 gene who do not develop PD but other neurological syndromes, we hypothesize that some other feature must be added to trigger the disease, such as disturbances in protein homeostasis.
The most neuropathologically interesting aspect of the new MCI-Park model is that reduced release of dopamine from axons terminating in the target area of substantia nigra neurons in the basal ganglia (striatum) is not sufficient to trigger the Parkinsonian-type disturbances in the animals' locomotion. Local release of dopamine from dendrites within the substantia nigra must also be affected (see figure below). Therefore, in the context of therapeutic strategies, it does not seem sufficient to try to normalize dopamine levels in the striatum alone.
In summary, based on the data obtained in the MCI-Park model, there is now strong evidence for the involvement of NADH dehydrogenase (MCI or complex I) in the pathogenesis of Parkinson's disease. The reduced release of dopamine in both groups of neuronal projections, dendrites and axons, during the course of mitochondrial disorders then leads to the known motor deficits.
References:
González-RodrÃguez P, Zampese E, Stout KA, Guzman JN, Ilijic E, Yang B, Tkatch T, Stavarache MA, Wokosin DL, Gao L, Kaplitt MG, López-Barneo J, Schumacker PT, Surmeier DJ (2021) Disruption of mitochondrial complex I induces progressive parkinsonism. Nature 599:650-656
Surmeier DJ, Obeso JA, Halliday GM (2017) Selective neuronal vulnerability in Parkinson disease. Nature Reviews Neuroscience 18:101-113