Parkinson's disease (PD) is an age-related neurodegenerative disorder that affects approximately 1 million persons in the United States. It is characterized by resting tremor, rigidity, bradykinesia or slowness, gait disturbance, and postural instability. Pathological features include degeneration of dopaminergic neurons in the substantia nigra pars compacta coupled with intracytoplasmic inclusions known as Lewy bodies. Neurodegeneration and Lewy bodies can also be found in the locus ceruleus, nucleus basalis, hypothalamus, cerebral cortex, cranial nerve motor nuclei, and central and peripheral components of the autonomic nervous system. Current treatment consists of a dopamine replacement strategy using primarily the dopamine precursor levodopa. While levodopa provides benefit to virtually all PD patients, after 5-10 years of treatment the majority of patients develop adverse events in the form of dyskinesia (involuntary movements) and fluctuations in motor response. Further, disease progression is associated with the development of dementia, autonomic dysfunction, and postural instability, which do not respond to levodopa therapy. Accordingly, research efforts have been directed toward understanding the etiology and pathogenesis of PD in the hope of developing a more effective therapy that will slow or halt the natural progression of PD. This paper reviews recent advances.

Etiology and pathogenesis of Parkinson's disease.

Monoamine oxidase inhibitors were among the first antidepressants to be discovered and have long been used as such. It now seems that many of these agents might have therapeutic value in several common neurodegenerative conditions, independently of their inhibition of monoamine oxidase activity. However, many claims and some counter-claims have been made about the physiological importance of these enzymes and the potential of their inhibitors. We evaluate these arguments in the light of what we know, and still have to learn, of the structure, function and genetics of the monoamine oxidases and the disparate actions of their inhibitors.

The therapeutic potential of monoamine oxidase inhibitors.

Mitochondria play a central role in the survival and death of neurons. The detailed bioenergetic mechanisms by which isolated mitochondria generate ATP, sequester Ca2+, generate reactive oxygen species, and undergo Ca2+-dependent permeabilization of their inner membrane are currently being applied to the function of mitochondria in situ within neurons under physiological and pathophysiological conditions. Here we review the functional bioenergetics of isolated mitochondria, with emphasis on the chemiosmotic proton circuit and the application (and occasional misapplication) of these principles to intact neurons. Mitochondria play an integral role in both necrotic and apoptotic neuronal cell death, and the bioenergetic principles underlying current studies are reviewed.

https://www.physiology.org/doi/pdf/10.1152/physrev.2000.80.1.315

Mitochondria and Neuronal Survival

Mitochondria as regulators of apoptosis: doubt no more

Arsenic Trioxide Selectively Induces Acute Promyelocytic Leukemia Cell Apoptosis Via a Hydrogen Peroxide-Dependent Pathway

Studies in non-neural cells have suggested that a fall in mitochondrial membrane potential (ΔΨM) is one of the earliest events in apoptosis. It is not known whether neural apoptosis caused by nerve growth factor (NGF) and serum withdrawal involves a decrease in ΔΨM. We used epifluorescence and laser confocal microscopy with the mitochondrial potentiometric dyes chloromethyl-tetramethylrosamine methyl ester and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethybenzimidazol carbocyanine iodide to estimate ΔΨM. PC12 cells were differentiated in media containing serum and NGF for 6 d before withdrawal of trophic support. After washing, the cells were incubated with media containing serum and NGF (M/S+N), media without serum and NGF, or media with the “trophic-like” monoamine oxidase B inhibitor, (−)-deprenyl. Mitochondria in cells without trophic support underwent a progressive shift to lower ΔΨM values that was significant by 3 hr after washing. The percentages of cells with nuclear chromatin condensation or nuclear DNA fragmentation were not significantly increased above those for cells in M/S+N until 6 hr after washing. Replacement of cells into M/S+N or treatment with (−)-deprenyl markedly reduced the proportion of mitochondria with decreased ΔΨM. Measurements of cytoplasmic peroxyl radical levels with 2′,7′-dihydrodichlorofluorescein fluorescence and intramitochondrial Ca2+ with dihydro-rhodamine-2-acetylmethyl ester indicated that cytoplasmic peroxyl radical levels were not increased until after 6 hr, whereas increases in intramitochondrial Ca2+ paralleled the decreases in ΔΨM. (−)-Deprenyl appeared to alter the relationship between intramitochondrial Ca2+ levels and ΔΨM, possibly through its reported capacity to increase the synthesis of proteins such as BCL-2.

https://www.jneurosci.org/content/jneuro/18/3/932.full.pdf

Mitochondrial Membrane Potential and Nuclear Changes in Apoptosis Caused by Serum and Nerve Growth Factor Withdrawal: Time Course and Modification by (−)-Deprenyl

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Mitochondrial Membrane Potential and Nuclear Changes in Apoptosis Caused by Serum and Nerve Growth Factor Withdrawal: Time Course and Modification by (−)-Deprenyl