hdac6 bridges the gap

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Researchers at Duke University (NC,USA) have identified a crucial step in apotential mechanism for the formationof inclusion bodies in neurodegen-erative diseases. Tso-Pang Yao and co-workers have shown that an enzyme,HDAC6, provides an all important linkbetween ubiquitinated proteins anddynein. HDAC6 initiates the transportof misfolded proteins or their aggre-gates tagged for degradation to inclus-ion bodies called aggresomes via themicrotubule network.

Aggresomes, which resemble theLewy bodies found in patients withParkinson’s disease (PD), are formedwhen the proteasome—the normal siteof protein degradation—is unable tocope with an excess of misfolded pro-teins. “Our results provide a molecularmechanism for understanding howcells recognise and transport potentiallytoxic misfolded proteins to the aggre-some for processing”, explains Yao.

The researchers found that treat-ment of cells with the proteasomeinhibitor MG132 resulted in localisa-tion of HDAC6 to a single aggresome-like inclusion body that was locatedclose to the microtubule organisingcentre or centrosome (Cell 2003; 115:727–38). In the presence of MG132,HDAC6 could bind to both poly-ubiquitinated CFTR-�F508, a mutatedform of cystic fibrosis transmembraneconducting regulator, and dynein.Indeed, when HDAC6 expression wasreduced by use of an RNA knockdowntechnique, the amount of poly-ubiquitinated proteins bound to dyneinwas reduced, aggresome formation wasinhibited, and apoptotic cell death wasinduced.

Yao and co-workers also found thatHDAC6 is present in Lewy bodies inthe brains of patients with PD ordementia with Lewy bodies. “Theobservation that HDAC6 deficiency

leads to defective aggresome formationand elevated sensitivity to misfoldedprotein accumulation supports thehypothesis that inclusion bodies, such as the Lewy body, are part of a cytoprotective response to theaccumulation of toxic misfoldedproteins”, says Yao. “Our results wouldsuggest that enhancing the enzymaticactivity of HDAC6 might facilitate theclearance of toxic misfolded proteinsand therefore be beneficial in thetreatment of PD.”

Kevin McNaught (Mount SinaiSchool of Medicine, New York, NY,USA) agrees: “Future studies willprovide a better understanding of themechanism by which aggresomes andLewy bodies are formed, and theirrelevance to the pathogenesis ofneurodegenerative disorders that areincreasingly being associated withaltered proteolysis.”Rebecca Love

HDAC6 bridges the gap

THE LANCET Neurology Vol 3 February 2004 http://neurology.thelancet.com76

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Reduced glucose metabolism: an early sign of Alzheimer’s?Young adults who carry the apo-lipoprotein E (APOE) �4 allele showsigns of reduced glucose metabolismin the same brain areas as older �4carriers who have already developedAlzheimer’s disease (AD). Bothgroups have abnormally low cerebralglucose metabolism in the posteriorcingulate, parietal, temporal, andprefrontal cortex. “These findingsraise several interesting and importantquestions”, say lead author EricReiman (Banner Good SamaritanMedical Center and University ofArizona, Phoenix, AZ, USA) andcoauthor Richard Caselli (MayoClinic, Scottsdale, AZ, USA). “Howearly before or after birth are theinitial brain changes seen in thosesusceptible to AD? How are thesebrain changes related to thesubsequent neuropathological andprogressive metabolic abnormalitiesfound in AD? Can these brain changesbe targeted by an extremely safe andwell tolerated prevention therapy?”

Reiman, Caselli, and colleaguescharacterised the APOE genotype of

135 healthy volunteers (aged 20–39).12 of the volunteers were carriers ofthe �4 allele, who were selected forfurther study along with 15 controlindividuals who did not carry the �4allele. The control group included 12adults matched for age, sex, andeducational level to the 12 �4 carriers.Each person was asked for a detailedmedical and family history andreceived a neurological examinationand a structured psychiatric interviewbefore undergoing PET scanning toassess brain glucose metabolism.None of the people were told theirgenotype. The �4 carriers did notdiffer from their counterparts in anytest except for the PET scan, whichshowed that their glucose metabolismwas abnormally low (Proc Natl AcadSci USA 2004; 101: 284–89).

Bill Thies of the Alzheimer’sAssociation (Silver Spring, MD, USA)comments that the study of glucoseprocessing in the brains of individualswho are known to have a geneticpredisposition to AD is a promisingavenue to follow in the search for

early clinical events of the disease.However, he warns that “althoughthere is a correlation between glucose metabolism pathology, it is too early to say yet whether it iscausative”.

According to Reiman, furtherwork is already underway to clarifyand expand on these results. He andhis colleagues at the TranslationalGenomics Research Institute and theArizona Alzheimer’s Disease Centerare using brain tissue from patientswith AD and cognitively normal braindonors to investigate which genes arepreferentially turned on and off in themetabolically affected brain regions.“One of our aims will be tocharacterise the brain changesresponsible for the early metabolicabnormalities, providing newinformation about the earliest brainchanges involved in the susceptibilityto AD and new targets against whichone might aim drugs for thetreatment and prevention of AD”, hesays.Kathryn Senior