The paper is very fascinating and opens up new avenues in Parkinson research.

Recently, Fountaine and his coworkers published a paper in J. Neurochem. Res. which is also very interesting. They developed a system in which levels of α-synuclein can be acutely suppressed by using RNA interference (RNAi) in a physiologically relevant human dopaminergic cellular model. By using small interfering RNA (siRNA) molecules targeted to endogenous α-synuclein, they achieved 80 percent protein knockdown. They also showed that α-synuclein knockdown has no effect on cellular survival either under normal growth conditions over 5 days or in the presence of the mitochondrial inhibitor rotenone.

Knockdown does, however, confer resistance to the dopamine transporter (DAT)-dependent neurotoxin N-methyl-4-phenylpyridinium (MPP[+]). Collectively, the data infers that α-synuclein suppression decreases dopamine transport in human cells, reducing the maximal uptake velocity (Vmax) of dopamine and the surface density of its transporter by up to 50 percent. But my thinking is how one can correlate...  Read more

The paper is very fascinating and opens up new avenues in Parkinson research.

Recently, Fountaine and his coworkers published a paper in J. Neurochem. Res. which is also very interesting. They developed a system in which levels of α-synuclein can be acutely suppressed by using RNA interference (RNAi) in a physiologically relevant human dopaminergic cellular model. By using small interfering RNA (siRNA) molecules targeted to endogenous α-synuclein, they achieved 80 percent protein knockdown. They also showed that α-synuclein knockdown has no effect on cellular survival either under normal growth conditions over 5 days or in the presence of the mitochondrial inhibitor rotenone.

Knockdown does, however, confer resistance to the dopamine transporter (DAT)-dependent neurotoxin N-methyl-4-phenylpyridinium (MPP[+]). Collectively, the data infers that α-synuclein suppression decreases dopamine transport in human cells, reducing the maximal uptake velocity (Vmax) of dopamine and the surface density of its transporter by up to 50 percent. But my thinking is how one can correlate those results with this paper? Do GPCR expression and dopamine transporters have a coupling effect or diverse effects? Do they take the direct or indirect pathway of neural transmission?

References:
Fountaine TM, Wade-Martins R. RNA interference-mediated knockdown of alpha-synuclein protects human dopaminergic neuroblastoma cells from MPP(+) toxicity and reduces dopamine transport. J Neurosci Res. 2006 Nov 27; [Epub ahead of print] Abstract

View all comments by Bharathi Shrikanth Gadad

Proteolytic processing of SDF-1 reveals a new receptor specificity mediating HIV-associated neurodegeneration
HIV-1 associated dementia (HAD) is characterized by a constellation of cognitive, behavioral, and/or motor abnormalities affecting a significant portion of infected children and adults with human immunodeficiency virus (HIV) (Ellis et al., 2002; Epstein and Gelbard, 1999; McArthur et al., 1999). Although the incidence of HAD has dropped to about 10 percent of all infected subjects with the advent of highly active antiretroviral therapy (HAART) (Sacktor et al., 2001), HAD remains a persistent problem in infected individuals as resistance to therapy grows with viral strain mutations and because of the limited ability of drugs to penetrate the blood-brain barrier. Thus, HAD will continue to be a significant complication of advanced HIV-1 disease (Carpenter et al., 2000; McArthur et al., 1999).

The pathological correlate of HAD, HIV-1 encephalitis (HIVE), is characterized by the presence of HIV-1-infected and immune-activated mononuclear phagocytes (MP,...  Read more

Proteolytic processing of SDF-1 reveals a new receptor specificity mediating HIV-associated neurodegeneration
HIV-1 associated dementia (HAD) is characterized by a constellation of cognitive, behavioral, and/or motor abnormalities affecting a significant portion of infected children and adults with human immunodeficiency virus (HIV) (Ellis et al., 2002; Epstein and Gelbard, 1999; McArthur et al., 1999). Although the incidence of HAD has dropped to about 10 percent of all infected subjects with the advent of highly active antiretroviral therapy (HAART) (Sacktor et al., 2001), HAD remains a persistent problem in infected individuals as resistance to therapy grows with viral strain mutations and because of the limited ability of drugs to penetrate the blood-brain barrier. Thus, HAD will continue to be a significant complication of advanced HIV-1 disease (Carpenter et al., 2000; McArthur et al., 1999).

The pathological correlate of HAD, HIV-1 encephalitis (HIVE), is characterized by the presence of HIV-1-infected and immune-activated mononuclear phagocytes (MP, brain macrophages, and microglia). The association among HIVE, inflammation, and neuronal injury is substantial (Glass et al., 1993). HIV-1-infected MPs secrete cytotoxic factors and viral proteins that cause synaptic damage, neuronal degeneration and cellular dropout (Gendelman, 1997; Gonzalez-Scarano and Martin-Garcia, 2005).

Dr. Richard Power’s group in Canada has been very active in elucidating the molecular mechanisms leading to neuronal cell injury and death in HAD and other neurodegenerative disorders. In 2003, they published a paper in Nature Neuroscience demonstrating that matrix metalloproteinase-2 (MMP-2), upregulated by HIV-1-infected macrophages, readily cleaves four amino acids from the N-terminal of stromal cell-derived factor 1 (SDF-1), the endogenous ligand for CXCR4, resulting in the formation of SDF-1 (5-67), which becomes a potent neurotoxin (Zhang et al., 2003). In the current publication they extended this previous finding and provided evidence demonstrating the presence of SDF-1 (5-67) in the brain of an HIV-1 dementia subject who died from this disease (Vergote et al., 2006). Further, they provided new evidence that SDF(5-67) changes the protein’s receptor specificity from the normal CXCR4 receptor to CXCR3. SDF(5-67)-mediated neurotoxicity is through CXCR3 instead of CXCR4, leading to neurodegeneration in HAD.

It is known that HIV-1-infected and/or immune-activated macrophages could regulate astrocyte SDF-1 production during HAD (Peng et al., 2006). The current finding indicates that SDF-1 produced from activated astrocytes could be potentially cleaved by MMP-2 released from infected and activated macrophages and the resulting SDF(5-67) could lead to mediated neurodegeneration. Similarly, microglia activation is an important feature of Alzheimer disease (AD) and is likely to be a key participant in disease progression. Although the etiology and neuropathology of HAD and AD are clearly distinct, common features of both diseases are microglial activation, brain inflammation, and neuronal injury (Cotter et al., 1999). While neuronal cell injury and death is likely, the molecular mechanisms leading to this pathology remain poorly understood. Although further studies are needed, it is quite possible that similar phenomena happen in the AD brain regarding SDF-1 production, SDF-1 cleavage, and SDF-1 fragment-mediated neurodegeneration. This investigation could provide new therapeutic avenues for the treatment of HAD and possibly AD.

Although this remains an important area of investigation, many questions remain to be answered. First: Is activated MMP-2 the only enzyme responsible for cleavage of SDF-1 to SDF(5-67) or other fragments? Second: What factors would cause the activation of MMP-2, initiating the cleavage of SDF-1 and the increase of SDF(5-67)? Third: Why does there appear to be more SDF(5-67) in HAD samples than in non-demented subjects? How is the increase in SDF(5-67) related to HAD? Is there cause and effect? And last and most importantly, how is SDF(5-67) involved in activation of caspase-3 and p53 pathways, which lead to neuronal apoptosis? What are the upstream signaling pathways for these activations? Further investigation of these questions will not only help to elucidate the mechanism in HAD, but also provide new avenues for the investigation of neuronal injury mechanisms in other neurodegenerative diseases such as AD.

References:
Carpenter CC, Cooper DA, Fischl MA, Gatell JM, Gazzard BG, Hammer SM, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JS, Richman DD, Saag MS, Schechter M, Schooley RT, Thompson MA, Vella S, Yeni PG, Volberding PA. Antiretroviral therapy in adults: updated recommendations of the International AIDS Society-USA Panel. JAMA. 2000 Jan 19;283(3):381-90. Review. Abstract

Cotter, R., Zheng, J., and Gendelman, H. E. (1999). The role of mononuclear phagocytes in neurodegenerative disorders: Lessons from multiple sclerosis, Alzheimer's disease and HIV-1 dementia. In Advances in Neurodegenerative Disorders, J. Marwah, and H. Teitelbaum, eds. (Scottsdale, AZ, Prominent Press), pp. 203-241.

Ellis RJ, Moore DJ, Childers ME, Letendre S, McCutchan JA, Wolfson T, Spector SA, Hsia K, Heaton RK, Grant I. Progression to neuropsychological impairment in human immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human immunodeficiency virus RNA. Arch Neurol. 2002 Jun;59(6):923-8. Abstract

Epstein LG, Gelbard HA. HIV-1-induced neuronal injury in the developing brain. J Leukoc Biol. 1999 Apr;65(4):453-7. Review. Abstract

Gendelman, H. E. (1997). The Neuropathogenesis of HIV-1-Dementia. In The neurology of AIDS, H. E. Gendelman, S. A. Lipton, L. G. Epstein, and S. Swindells, eds. (New York, Chapman and Hall), pp. 1-10.

Glass JD, Wesselingh SL, Selnes OA, McArthur JC. Clinical-neuropathologic correlation in HIV-associated dementia. Neurology. 1993 Nov;43(11):2230-7. Abstract

Gonzalez-Scarano F, Martin-Garcia J. The neuropathogenesis of AIDS. Nat Rev Immunol. 2005 Jan;5(1):69-81. Review. Abstract

McArthur JC, Sacktor N, Selnes O. Human immunodeficiency virus-associated dementia. Semin Neurol. 1999;19(2):129-50. Review. Abstract

Peng H, Erdmann N, Whitney N, Dou H, Gorantla S, Gendelman HE, Ghorpade A, Zheng J. HIV-1-infected and/or immune activated macrophages regulate astrocyte SDF-1 production through IL-1beta. Glia. 2006 Nov 1;54(6):619-29. Abstract

Sacktor N, Lyles RH, Skolasky R, Kleeberger C, Selnes OA, Miller EN, Becker JT, Cohen B, McArthur JC; Multicenter AIDS Cohort Study. HIV-associated neurologic disease incidence changes: Multicenter AIDS Cohort Study, 1990-1998. Neurology. 2001 Jan 23;56(2):257-60. Abstract

Vergote D, Butler GS, Ooms M, Cox JH, Silva C, Hollenberg MD, Jhamandas JH, Overall CM, Power C. Proteolytic processing of SDF-1{alpha} reveals a change in receptor specificity mediating HIV-associated neurodegeneration. Proc Natl Acad Sci U S A. 2006 Dec 5; [Epub ahead of print] Abstract

Xiong H, Zeng YC, Lewis T, Zheng J, Persidsky Y, Gendelman HE. HIV-1 infected mononuclear phagocyte secretory products affect neuronal physiology leading to cellular demise: relevance for HIV-1-associated dementia. J Neurovirol. 2000 May;6 Suppl 1:S14-23. Review. Abstract

Zhang K, McQuibban GA, Silva C, Butler GS, Johnston JB, Holden J, Clark-Lewis I, Overall CM, Power C. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Nat Neurosci. 2003 Oct;6(10):1064-71. Epub 2003 Sep 21. Abstract

View all comments by Jialin Zheng