Calcium, Bioenergetics, and Neuronal Vulnerability in Parkinson's Disease

Abstract

The most distinguishing feature of neurons is their capacity for regenerative electrical activity. This activity imposes a significant mitochondrial burden, especially in neurons that are autonomously active, have broad action potentials, and exhibit prominent Ca 2؉ entry. Many of the genetic mutations and toxins associated with Parkinson's disease compromise mitochondrial function, providing a mechanistic explanation for the pattern of neuronal pathology in this disease. Because much of the neuronal mitochondrial burden can be traced to L-type voltagedependent channels (channels for which there are brain-penetrant antagonists approved for human use), a neuroprotective strategy to reduce this burden is available.

Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation

“…As the result of these characteristics, the high neural activity, the accumulation of biogenic dopamine metabolites and other reactive oxygen species, and the alteration of calcium homeostasis may make the SNpc DA neurons more vulnerable to PD-related degeneration (31)(32)(33). In addition, DA neurons residing in different subdivisions of SNpc also display differential vulnerability in PD (2-4).…”

Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration

“…High ATP is required in DA neurons, for example, for the vesicular monoamine transporter, VMAT2, responsible for the dopamine uptake into presynaptic vesicles, to decrease the toxic oxidation-prone cytosolic dopamine and for removing the toxic amounts of calcium from the cytosol to the endoplasmic reticulum by high-affinity ATP-dependent transporters. Calcium gets into the cell by the sustained pacemaking activity of the l-type Ca v 1.3 calcium channels in adult mice (30,41). Therefore, reduced ATP levels might alter the total DA network, which controls many Histology and immunohistochemistry.…”

Soluble, Prefibrillar α-Synuclein Oligomers Promote Complex I-dependent, Ca2+-induced Mitochondrial Dysfunction

“…Markers of mitochondrial oxidative stress, including oxidized complex I subunits (22) and mitochondrial DNA mutations (23), are also elevated in PD patients, although it is unclear whether these are a cause or consequence of ETC dysfunction. The neuronal populations most impaired in PD, including the substantia nigra pars compacta, locus ceruleus, and dorsal motor nucleus of the vagus, share an unusual phys-iological phenotype; they consist primarily of broad-spike pacemaking neurons with high transmembrane Ca 2ϩ currents and low Ca 2ϩ buffering capacities (24). This combination places a great metabolic burden on mitochondria to continually reestablish the resting cytosolic Ca 2ϩ concentration.…”