. Altered cholesterol metabolism in Niemann-Pick type C1 mouse brains affects mitochondrial function. J Biol Chem. 2005 Mar 25;280(12):11731-9. PubMed.


Please login to recommend the paper.


  1. It is always fascinating to think why, in neurodegenerative disorders characterized by the loss of neurons in completely different regions, the signs of neuronal dysfunction are similar. Why do neurons display similar symptoms of degeneration despite very different causes of disease? Is there some critical and unifying factor(s) that if affected, no matter through which pathway, will force the neuron to die? That was a question that has driven my work since we discovered that a defect in axonal trafficking is an early event in pathology in Huntington disease (Trushina et al., 2004). At that time, it was also known that axonal trafficking was altered in Alzheimer disease and ALS (Collard et al., 1995; Drouet et al., 2000). Finding similarity in the mechanisms gives hope that we may find a cure that could help in multiple diseases. But this is not so simple—we still do not know the precise order of events, their timing, what are the causes and what are the consequences. In the case of mitochondrial dysfunction and neurodegenerative diseases, we do not know whether mutant proteins affect the motors necessary to transport the organelles, causing a slowing down of mitochondrial transport and the subsequent loss of energy supply to the distant part of neurons, or whether additional pathways exist that affect mitochondria function independently.

    Thus, it is very interesting to follow the emerging data suggesting that a small molecule plays a big role in neurons, in their health and death. Surprisingly, there is still no definitive data that would, in detail, explain how neurons handle their cholesterol reserve; does it come from supporting glia cells, is it synthesized internally, or is there a fine balance between both ways (for more details see publications of Dr. F.W. Pfrieger)? But it is a very important finding that any alteration in the levels of cholesterol in neurons could cause neurodegeneration (Koudinov and Koudinova, 2001). Our recent study in Huntington disease also strongly supports the idea of cholesterol involvement in HD pathology. The paper of Yu et al. is an additional demonstration of the devastation that defects in cholesterol metabolism could cause neurons in another neurodegenerative disorder—Niemann-Pick type C1 (NPC1). This paper elegantly ties together neurons, cholesterol, mitochondrial defects, and neurodegeneration. It will be interesting to check whether similar defects, with cholesterol accumulation in mitochondria membranes, exist in other diseases known to have mitochondrial dysfunction. Could the unifying factor in neurodegeneration be cholesterol?


    . Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol. 2004 Sep;24(18):8195-209. PubMed.

    . Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis. Nature. 1995 May 4;375(6526):61-4. PubMed.

    . Molecular basis of Alzheimer's disease. Cell Mol Life Sci. 2000 May;57(5):705-15. PubMed.

    . Essential role for cholesterol in synaptic plasticity and neuronal degeneration. FASEB J. 2001 Aug;15(10):1858-60. PubMed.

Make a Comment

To make a comment you must login or register.