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Alpha-synuclein and Parkinson's disease

Introduction to Parkinson's disease

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Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. It is characterised by the loss of pigmented neurons in a region of the brain called the substantia nigra. These neurons produce a neurotransmitter called dopamine, which is important for the control of movement. Loss of these neurons results in a reduction of the amount of dopamine in the brain, causing a range of symptoms including bradykinesia, rigidity and resting tremor.

Pathology of Parkinson's disease

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The two major pathological features of Parkinson's disease are:

  1. Degeneration of pigmented neurons in the substantia nigra [1].
  2. Presence of Lewy bodies in the remaining pigmented neurons in the substantia nigra and in other affected regions of the brain [2][3][4]. A major component of Lewy bodies is a protein called alpha-synuclein[5].

Alpha-synuclein

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In humans, alpha-synuclein is produced via transcription of the SNCA gene, which is located on chromosome 4q21[6]. It is a small, soluble protein found within a number of brain regions including the neocortex, hippocampal formation, amygdala, nucleus accumbens, striatum, thalamus and olfactory bulb[7][8]. It is found within the presynaptic terminals of mature neurons, closely associated with syaptic vesicles[9][10], and may also be found in non-neuronal cells such as glia[11]. The function of this protein is not fully understood, however it has been shown to be involved in the regulation of dopamine[12].

Alpha-synuclein and Parkinson's disease

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In Parkinson's disease, alpha-synuclein undergoes conformational changes that result in the formation of aggregates in neuronal cell bodies (Lewy bodies) and cell processes (Lewy neurites)[13]. The location of alpha-synuclein in the brain also changes. Current evidence suggests that in the first stages of the disease, Lewy pathology is mainly found within the olfactory bulb and caudal brainstem, ascending into the brain affecting the substantia nigra by stage 3 and neocortex by stages 5 and 6[14].

References

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  1. ^ WOLTERS, E. & BRAAK, H. (2006) Parkinson's disease: premotor clinico-pathological correlations. Journal of Neural Transmission, Suppl. 309-319.
  2. ^ DUNNETT, SB. & BJORKLUND, A. (1999) Prospects for new restorative and neuroprotective treatments in Parkinson's disease. Nature, 399, A32-39.
  3. ^ GELB, DOUGLAS J., OLIVER, EUGENE & GILMAN, SID. (1999) Diagnostic Criteria for Parkinson Disease. Archives of Neurology, 56, 33-39.
  4. ^ GOMEZ-TORTOSA, E., NEWELL, K., IRIZARRY, M., ALBERT, M., GROWDON, J. & HYMSN, B. (1999) Clinical and quantitative pathologic correlates of dementia with Lewy bodies. Neurology, 53, 1284-1291.
  5. ^ CROWTHER, R., DANIEL, S. & GOEDERT, M. (2000) Characterisation of isolated [alpha]-synuclein filaments from substantia nigra of Parkinson's disease brain. Neuroscience Letters, 292, 128-130.
  6. ^ XIA, Y., SAITOH, T., UEDA, K., TANAKA, S., CHEN, X., HASHIMOTO, M., HSU, L., CONRAD, C., SUNDSMO, M., YOSHIMOTO, M., THAL, L., KATZMAN, R. & MASLIAH, E. (2001) Characterization of the human alpha-synuclein gene: genomic structure, transcription start site, promoter region and polymorphisms. Journal of Alzheimer's Disease, 3, 485-494.
  7. ^ BRAAK, H., DEL TREDICI, K., GAI, W. & BRAAK, P. (2000) Alpha-synuclein is not a requisite component of synaptic boutons in the adult human central nervous system. Journal of Chemical Neuroanatomy, 20, 245-252.
  8. ^ YU, S., UEDA, K. & CHAN, P. (2005) Alpha-synuclein and dopamine metabolism. Molecular Neurobiology, 3, 243-254.
  9. ^ IWAI, A., MASLIAH, E., YOSHIMOTO, M., GE, N., FLANAGAN, L., DE SILVA, H., KITTEL A. & SAITOH. (1995) The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron, 14, 467-475.
  10. ^ MAROTEAUX, L., CAMPANELLI, J. & SCHELLER, R. (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. Journal of Neuroscience, 8, 335-343.
  11. ^ MORI, F., TANJI, K., YOSHIMOTO, M., TAKAHASHI, H. & WAKABAYASHI, K. (2002) Demonstration of alpha-synuclein immunoreactivity in neuronal and glial cytoplasm in normal human brain tissue using proteinase K and formic acid pretreatment. Experimental Neurology, 176, 98-104.
  12. ^ PEREZ, R., WAYMIRE, J., LIN, E, LIU, J., GUO, F. & ZIGMOND, M. (2002) A Role for alpha -Synuclein in the Regulation of Dopamine Biosynthesis. Journal of Neuroscience., 22, 3090-3099.
  13. ^ FUJIWARA, H., HASEGAWA, M., DOHMAE, N., KAWASHIMA, A., MASLIAH, E., GOLDBERG, M., SHEN, J., TAKIO, K. & IWATSUBO, T. (2002) Alpha-synuclein is phosphorylated in synucleinopathy lesions. Nature Cell Biology, 4, 160-164.
  14. ^ BRAAK, H., TREDICI, K., RÜB, U., DE VOS, R., JANSEN STEUR, E. & BRAAK, E. (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiology of Aging, 24, 197-211.
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