Moussa B. H. Youdim

PGC-1α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease

Abnormal expression of genes for energy regulation in Parkinson’s disease patients identifies a master regulator as a possible therapeutic target for early intervention. Getting to the Root of Parkinson’s Disease Parkinson’s disease (PD) is a debilitating neurodegenerative disorder that results in the loss of dopamine neurons in the substantia nigra of the brain. Degeneration of these movement-related neurons predictably causes rigidity, slowness of movement, and resting tremor, but patients also show cognitive changes. Although gene mutations have been identified in several families with PD, the cause of the more common sporadic form is not known. Certain environmental factors, such as exposure to the pesticide rotenone, combined with a genetic susceptibility, are thought to confer risk for developing PD. A key pathological feature seen in postmortem brain tissue from PD patients is Lewy bodies, neuronal inclusions containing clumps of the α-synuclein protein (which is mutated in familial PD), as well as damaged mitochondria. Taking a systems biology approach to pinpoint the root cause of PD, Zheng et al. now implicate altered activity of the master transcription factor PGC-1α and the genes it regulates in the early stages of PD pathogenesis. To detect new sets of genes that may be associated with PD, the investigators did a meta-analysis of 17 independent genome-wide gene expression microarray studies that had been performed on a total of 322 postmortem brain tissue samples and 88 blood samples. The samples came from presymptomatic and symptomatic PD patients, as well as from control individuals who did not show any neurological deficits at autopsy. Nine genome-wide expression studies were conducted either on dopaminergic neurons obtained by laser capture from substantia nigra (three studies) or on substantia nigra homogenates (six studies). The authors then used a powerful tool called Gene Set Enrichment Analysis to sift through 522 gene sets (a gene set is a group of genes involved in one biological pathway or process). At the end of this tour-de-force analysis, they identified 10 gene sets that were all associated with PD. The gene sets with the strongest association contained nuclear genes encoding subunits of the electron transport chain proteins found in mitochondria. These genes all showed decreased expression in substantia nigra dopaminergic neurons (obtained by laser capture) even in the earliest stages of PD. Furthermore, a second gene set associated with PD and also underexpressed in the earliest stages of PD encodes enzymes involved in glucose metabolism. These results are compelling because many studies have already implicated dysfunctional mitochondria and altered energy metabolism as well as defective glucose metabolism in PD. The authors realized that these gene sets had in common the master transcriptional regulator, PGC-1α, and surmised that disruption of PGC-1α expression might be a root cause of PD. They tested this hypothesis in cultured dopaminergic neurons from embryonic rat midbrain forced to express a mutant form of α-synuclein. Overexpression of PGC-1α in these neurons resulted in activation of electron transport genes and protection against neuronal damage induced by mutant α-synuclein. In other cultured neurons treated with rotenone, overexpression of PGC-1α also was protective, blocking pesticide-induced neuronal cell death. These exciting findings identify altered expression of PGC-1α and the genes it regulates as key players during early PD pathogenesis. This potential new target could be exploited therapeutically to interfere with the pathological process during the earliest stages before permanent damage and neuronal loss occurs. Parkinson’s disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson’s and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson’s disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson’s disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson’s disease identifies PGC-1α as a potential therapeutic target for early intervention.

Neuromelanin may Mediate Neurotoxicity via its Interaction with Redox Active Iron

Neuromelanin (NM) is a complex polymer pigment found in catecholaminergic neurons of the human brain. The palour of the parkinsonian substantia nigra (SN) is one of the most characteristic pathological features of this disorder. A direct relationship between the loss of the dopaminergic SN cells and their NM content has been reported, while other work suggests that NM may play a protective function within the cell. Evidence to date suggests that NM is capable of acting as a protective mechanism within the cell via its ability to bind a variety of potentially toxic substances, such as exogenous cytotoxins and heavy metals, and via its ability to inactivate damaging free radicals; on the other hand, in the presence of increased tissue iron NM appears to potentiate cell damage. This is particularly relevant because iron is increased in the parkinsonian SN; the interaction between the increased tissue iron and NM may result in an increased rate of free radical production, leading to dopaminergic cell loss.

Brain Iron and other Trace Metals in Neurodegenerative Diseases

Iron is the most abundant metal in the human body and the brain, like the liver, contains a substantially higher concentration of iron than of any other metal (Yehuda and Youdim, 1988). It is an essential participant in many metabolic processes including a) DNA-, RNA- and protein synthesis, b) as a cofactor of many haem and non-haem enzymes, c) the formation of myelin and d) the development of the neuronal dendritic tree (Youdim et al., 1991). Within the brain, iron shows an uneven distribution with high levels in the basal ganglia (substantia nigra, putamen, caudate nucleus, globus pallidus), the red nucleus, and the dentate nucleus (e.g. Riederer et al., 1989). Iron deposition in the brain is mainly in organic storage forms such as ferritin but not haemosiderin (Octave et al., 1983) with relatively little in a free and reactive form. Unlike other tissues, the turnover of brain iron is extremely slow and serum iron has little access to it (Youdim, 1985). All the iron that is present in the brain is deposited before the closure of blood-brain barrier, whereas it is tightly regulated and highly sequestered.

Neuroprotective Actions of Green Tea Polyphenol, (-)-Epigallocatechin-3-Gallate in Models of Parkinson’s Disease: Gene Targets

Biochemical evidence points to central roles for oxidative stress (OS) and inflammation in neuronal death in both idiopathic and animal models of Parkinson’s disease (PD). Reports from our laboratory, as supported by others, point to the presence of ongoing OS and inflammatory processes occurring selectively in the substantia nigra pars compacta (SNPC) of parkinsonian brains and in animal models of PD.1–4 Therefore, drugs that exhibit free radical-scavenging and iron chelating properties, may serve as potential candidates for the treatment of PD.

Iron and Parkinson’s Disease

It is difficult to accept the idea that iron, the most prevalent and most utilized transition metal in the body, could be a hazardous factor for brain function related to neurodegenerative diseases, such as Parkinson’s disease, Alzheimer’s disease, trauma, and brain ischaemia. Nevertheless, abnormalities of iron metabolism (iron deficiency and iron overload) represent the largest metabolic disorders in medicine (see Lauffer, 1992, for review). Indeed, iron plays a crucial role in some of the most important biochemical processes in the body as well as in some of the most deadly and widespread diseases in the world (Lauffer, 1992; Youdim, 1994). Its role in Parkinson’s disease has not escaped scrutiny since the first observation by Leheremitte et al. (1924), demonstrating a substantial increase of the iron content in Parkinsonian substantia nigra (SN). This has been confirmed repeatedly, for example, in a series of very recent studies which a variety of techniques including magnetic resonance imaging (MRI) for determination of iron have been used (see Youdim et al., 1993a).

Targeting dysregulation of brain iron homeostasis in ageing

Brain iron is an essential nutrient for multiple functions, including gene expression, DNA synthesis, neurotransmission, myelination, oxygen transport, storage and activation, mitochondrial electron transport, numerous important metabolic processes and cofactor for several key enzymes of neurotransmitter biosynthesis. On the other hand, many investigators, among them the late Mark Smith, who was a pioneer neuroscientist and prominent investigator with regards to brain oxidative stress (OS) and iron in Alzheimer’s disease, have identified iron as an highly reactive element that can promote OS processes within the brain and might increase the toxicity of environmental or endogenous toxins. It is suggested that iron accumulation in the brain is capable of initiating free-radical reactions, which subsequently induce progressive loss of neurons, followed by a decrement in neuronal function characteristic of the ageing process. Indeed, it has become apparent that iron progressively accumulates in the brain as a function of age and that iron-induced OS can cause neurodegeneration. Chelation therapy was previously introduced as a novel therapy concept and rationale for the development of metal-binding drugs for neurodegeneration. The present review will discuss the involvement of dysregulation of brain iron homeostasis in the ageing process, addressing the potential importance of iron chelating therapeutic approaches.

Discussion: Session 5 — 8 P.M. - 8 February 1993

After Olanow’s paper, Baimbridge (Vancouver) asked why manganese intoxication as a pallidal disease is not a hyperkinetic movement disorder. Olanow said that if the dorsal pallidum is involved, hypokinesia appears.