Picking up the Pieces of Parkin - AlzForum Alzheimer Research Live Discussions

Three principal issues arise from the literature reviewed by Dr. Wolozin and his comments: (1) an evolving concept that previously separated forms of parkinsonism actually present heterogeneity of one and the same Parkinson's disease (PD) syndrome; (2) the role parkin - as a neural ubiquitin ligase - plays in the prevention of dopaminergic neurodegeneration in normal brain and in Lewy body inclusion formation during the pathogenesis of PD; and (3) the mechanism by which parkin identifies substrates that are destined to be degraded via the proteasomal pathway.

(1) Common Parkinson's disease syndrome? Research on the genotype of parkin vis a vis the phenotype of PD has clearly demonstrated that the strict separation of familial versus sporadic, and of young onset versus late onset PD, is a concept of the past. Ujike et al. (in No To Shinkei, 1999) and the landmark paper of Lücking et al. (in NEJM, 2000) clearly identified several cases with clinically "idiopathic" PD, i.e., no family history and no known consanguinity, that were caused by deletions in the parkin-gene in an autosomal recessive manner. Likewise several studies since then have confirmed these data and demonstrated isolated cases of late onset PD linked to parkin. Thus, we should probably from here on avoid the term "autosomal recessive juvenile parkinsonism" but rather refer to these parkin-linked cases as "heritable forms of PD". As such, they clearly comprise both sporadic and inherited subtypes with various ages of disease onset, and seem to account for approximately 50 per cent of all identifiable forms of autosomal recessive PD. This convergence of genotypes and phenotypes is reminiscent of several other polygenic syndromes, e.g., Alzheimer's disease or hyperlipidaemia.

(2) Complete versus partial loss of parkin's function ?Recently published research by Farrer et al (Annals of Neurol., 2001) represented another significant shift in PD dogmas. Previous reports indeed suggested that parkin-linked PD cases are devoid of the pathognomonic Lewy body (LB) inclusions that contain ubiquitin and alpha-synuclein (aS). However, Farrer and colleagues identified an individual who was a compound heterozygote at the parkin locus that carried LB in brainstem neurons. The unifying hypothesis we proposed is that the presence of residual parkin function (such as in Farrer's index patient 'Pw3') facilitates LB formation but is ultimately inefficient in the prevention of neurodegeneration. In contrast, loss of all parkin protein [and thus function - as was the case in the majority of the previously published LB-negative individuals that carried large parkin deletion mutations (Shimura et al., Science 2001 and references therein)] prevents the formation of LB inclusions (Schlossmacher et al., submitted). Such facilitation of insoluble inclusion formation by a neural ubiquitin ligase, E6-AP, has been demonstrated in an in vivo mouse model by Cummings et al. (Neuron, 2000). Furthermore, a partial loss of function (versus complete loss of function) of disease-linked proteins, e.g., dystrophin, has been identified as a key modulator of the resultant neurological phenotype, e.g. Becker versus Duchenne type of muscular dystrophy.

(3) Specific signal for substrate recognition by neural parkin ? As a rule of thumb, RING-dependent E3 ubiquitin ligases confer specificity for the substrates they recognize, bind and ubiquitinate by virtue of a distinct signal of their target proteins. Such is the case for c-cbl that facilitates degradation of phosphorylated membrane receptors to turn off important cellular signaling events (two papers by H. Band et al., J. Biol. Chem., 2000) or for the VHL E3 ligase complex that appears specific for the hydroxylation of a single proline residue (M. Ivan et al. and P.Jaakola et al., Science 2001). It will be important to determine whether the O-linked glycosylation of alpha-synuclein, which we recently identified in human brain (Shimura et al., 2001), serves as a shared posttranslational signal for proteins that are destined to be degraded via parkin's E3 ubiquitin ligase activity. Such insight may help to better understand the pathogenesis of the PD syndrome.

View all comments by Michael Schlossmacher