Substantia nigra, Parkinson’s disease

Fearnley, J. M. and Lees, A. J. (1991). Ageing and Parkinson s disease Substantia nigra regional selectivity. Brain 114(Pt. 5), 2283-2301. 

Mandel S, Grunblatt E, Riederer P, Amariglio N, Jacob-Hirsch J, Rechavi G, Youdim MB (2005) Gene expression profiling of sporadic Parkinson s disease substantia nigra pars compacta reveals impairment of ubiquitin-proteasome subunits, SKPIA, aldehyde dehydrogenase, and chaperone HSC-70. Ann N Y Acad Sci 1053 356-375. 

Neuromelanin, a dark colored pigment and product of the oxidative metabolism of dopamine, is found in the cytoplasm of dopaminergic neurons of the human substantia nigra pars compacta. Neuromelanin deposits increase with age, matching the age distribution of Parkinson s disease. In the absence of significant quantities of iron, neuromelanin can act as an antioxidant in... 

While advances in the symptomatic drug therapy (summarized below) have certainly improved the lives of many Parkinson patients, the goal of current research is to develop treatments that can prevent, retard or reverse the death of dopaminergic neurons in the substantia nigra pats compacta (and of other neurons involved in the pathogenesis of Parkinson s disease not mentioned in this essay). 

Adult dopamin-containing neurons in the substantia nigra rely on Cavl. 3 channels as pacemaker channels. It appears that the resulting enhanced Ca2+ load renders these channels more susceptible to neurotoxic effects and neurodegeneration as observed in Parkinson s disease. Preclinical evidence suggests that block of these with dihydropyridines causes a switch to a Cavl.3-independent pacemaker and protects these neurons from neurotoxicity. 

People with Parkinson s disease show a specific degeneration of the nigrostriatal tract so DA must be linked in some way to the control of motor function. It is also known that an imbalance of DA function on the two sides of the rat brain, either by stimulation or lesion of one SN, causes off-line or rotational movement (Ungerstadt and Arbuthnott 1970). This is best shown some days after 6-OHDA lesion of one substantia nigra and its nigrostriatal pathway when systemic apomorphine (DA agonist) causes animals to turn away from the lesioned side (contraversive), presumably... 

FIGURE 29-1. Anatomy of the extrapyramidal system. The extrapyramidal motor system controls muscle movement through a system of pathways and nerve tracts that connect the cerebral cortex, basal ganglia, thalamus, cerebellum, reticular formation, and spinal neurons. Patients with Parkinson s disease have a loss of dopamine neurons in the substantia nigra in the brain stem that leads to depletion of dopamine in the corpus striatum. The corpus striatum is made up of the caudate nucleus and the lentiform nuclei that are made up of the putamen and the globus pallidus. 

Unlike many chemicals in the brain, neurotransmitters are not homogeneously distributed, but concentrated in certain regions. For example, almost two-thirds of the dopamine in the brain is found in the bilateral nigrostriatal (mesostriatal) tract (pathway), where the neuronal cell bodies are located in the substantia nigra and the axons terminate in the corpus striatum. When over 85% of these dopaminergic neurons are lost, the characteristic motor dysfunction of Parkinson s disease is seen. 

Lewy body filaments are made of a-synuclein. Shortly after the identification of the genetic defect responsible for Parkinson s disease in the Contursi kindred, Lewy bodies and Lewy neurites in the substantia nigra from patients with sporadic Parkinson s disease were shown to be strongly immunoreactive for a-synuclein [7] (Fig. 45-3). Subsequently, Lewy body filaments were found to be... 

FIGURE 45-3 Substantia nigra from patients with Parkinson s disease immunostained for a-synuclein. (A) Two pigmented nerve cells, each containing an a-synuclein-positive Lewy body. Lewy neurites (small arrows) are also immunopositive. Scale bar 20 pm. (B) Pigmented nerve cell with two a-synuclein-positive Lewy bodies. Scale bar 8 pm. (C) a-Synuclein-positive extracellular Lewy body. Scale bar 4pm. 

The new work has established that a neurodegenerative pathway leading from soluble to insoluble, filamentous a-synuclein is central to Lewy body diseases and multiple system atrophy. The development of experimental models of a-synucleinopathies has opened the way to the identification of the detailed mechanisms by which the formation of inclusions causes disease. These model systems have also made it possible to identify disease modifiers that may well lead to the development of the first mechanism-based therapies for these diseases. At a conceptual level, it will be important to understand whether a-synuclein has a role to play in disorders, such as autosomal-recessive juvenile forms of parkinsonism caused by mutations in the Parkin, DJ-1 and PINK-1 genes, or whether there are entirely separate mechanisms by which the dopaminergic nerve cells of the substantia nigra degenerate in Parkinson s disease and in inherited disorders with parkinsonism. 

An inevitable consequence of ageing is an elevation of brain iron in specific brain regions, e.g. in the putamen, motor cortex, pre-frontal cortex, sensory cortex and thalamus, localized within H- and L-ferritin and neuromelanin with no apparent adverse effect. However, ill-placed excessive amounts of iron in specific brain cellular constituents, such as mitochondria or in specific regions brain, e.g. in the substantia nigra and lateral globus pallidus, will lead to neurodegenerative diseases (Friedreich s ataxia and Parkinson s disease (PD), respectively). We discuss here a few of the examples of the involvement of iron in neurodegenerative diseases. From more on iron metabolism see Crichton, 2001. 

Despite the misfortunes of these addicts, MPTP has proved an invaluable tool for studying the biology of Parkinson s disease. When MPTP is injected into experimental rats, mice, or monkeys, neurons in the substantia nigra of these animals start to die, and the animals develop motor problems that closely resemble the symptoms of Parkinson s disease. Researchers hope to use MPTP in animals to unravel the mystery of what causes Parkinson s disease in humans, in the hope that they can develop a cure for this devastating disease. 

It is widely accepted that Parkinson s disease primarily results from degeneration of pigmented neurons in the substantia nigra (Gibb 1998). This causes a loss of nigrostriatal projections and lack of dopamine modulation in the striatum. In addition to loss of neurons, many of the remaining neurons contain Lewy bodies. 

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