RGD Reference Report - Impaired balance of mitochondrial fission and fusion in Alzheimer's disease. - Rat Genome Database

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Impaired balance of mitochondrial fission and fusion in Alzheimer's disease.

Authors: Wang, X  Su, B  Lee, HG  Li, X  Perry, G  Smith, MA  Zhu, X 
Citation: Wang X, etal., J Neurosci. 2009 Jul 15;29(28):9090-103. doi: 10.1523/JNEUROSCI.1357-09.2009.
RGD ID: 7800727
Pubmed: PMID:19605646   (View Abstract at PubMed)
PMCID: PMC2735241   (View Article at PubMed Central)
DOI: DOI:10.1523/JNEUROSCI.1357-09.2009   (Journal Full-text)

Mitochondrial dysfunction is a prominent feature of Alzheimer's disease (AD) neurons. In this study, we explored the involvement of an abnormal mitochondrial dynamics by investigating the changes in the expression of mitochondrial fission and fusion proteins in AD brain and the potential cause and consequence of these changes in neuronal cells. We found that mitochondria were redistributed away from axons in the pyramidal neurons of AD brain. Immunoblot analysis revealed that levels of DLP1 (also referred to as Drp1), OPA1, Mfn1, and Mfn2 were significantly reduced whereas levels of Fis1 were significantly increased in AD. Despite their differential effects on mitochondrial morphology, manipulations of these mitochondrial fission and fusion proteins in neuronal cells to mimic their expressional changes in AD caused a similar abnormal mitochondrial distribution pattern, such that mitochondrial density was reduced in the cell periphery of M17 cells or neuronal process of primary neurons and correlated with reduced spine density in the neurite. Interestingly, oligomeric amyloid-beta-derived diffusible ligands (ADDLs) caused mitochondrial fragmentation and reduced mitochondrial density in neuronal processes. More importantly, ADDL-induced synaptic change (i.e., loss of dendritic spine and postsynaptic density protein 95 puncta) correlated with abnormal mitochondrial distribution. DLP1 overexpression, likely through repopulation of neuronal processes with mitochondria, prevented ADDL-induced synaptic loss, suggesting that abnormal mitochondrial dynamics plays an important role in ADDL-induced synaptic abnormalities. Based on these findings, we suggest that an altered balance in mitochondrial fission and fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction in AD brain.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alzheimer's disease  IEP 7800727; 7800727; 7800727protein:decreased expression:hippocampus (human)RGD 
Alzheimer's disease  ISODNM1L (Homo sapiens)7800727; 7800727protein:decreased expression:hippocampus (human)RGD 
Alzheimer's disease  IEP 7800727protein:increased expression:hippocampus (human)RGD 
Alzheimer's disease  ISOFIS1 (Homo sapiens)7800727; 7800727protein:increased expression:hippocampus (human)RGD 
Alzheimer's disease  ISOMFN1 (Homo sapiens)7800727; 7800727protein:decreased expression:hippocampus (human)RGD 
Alzheimer's disease  ISOMFN2 (Homo sapiens)7800727; 7800727protein:decreased expression:hippocampus (human)RGD 
Alzheimer's disease  IEP 7800727protein:decreased expression:brainRGD 
Alzheimer's disease  ISOOPA1 (Homo sapiens)7800727; 7800727protein:decreased expression:brainRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

Objects Annotated

Genes (Rattus norvegicus)
Dnm1l  (dynamin 1-like)
Fis1  (fission, mitochondrial 1)
Mfn1  (mitofusin 1)
Mfn2  (mitofusin 2)
Opa1  (OPA1, mitochondrial dynamin like GTPase)

Genes (Mus musculus)
Dnm1l  (dynamin 1-like)
Fis1  (fission, mitochondrial 1)
Mfn1  (mitofusin 1)
Mfn2  (mitofusin 2)
Opa1  (OPA1, mitochondrial dynamin like GTPase)

Genes (Homo sapiens)
DNM1L  (dynamin 1 like)
FIS1  (fission, mitochondrial 1)
MFN1  (mitofusin 1)
MFN2  (mitofusin 2)
OPA1  (OPA1 mitochondrial dynamin like GTPase)


Additional Information