The important question when thinking about the exciting identification of ATP13A2 mutations by Ramirez and others is: is this Parkinson disease? The Kufor-Rakeb syndrome is reported to have many of the features of parkinsonian disorders, including bradykinesia and a response of the extrapyramidal signs to L-DOPA. However, the disease also has several other components that distinguish it from typical PD, such as spasticity, vertical gaze defects, as well as dementia. Some of these signs are so unusual that it has been suggested that the disease is regarded as nosologically distinct from PD, and put into a category with other rare inherited diseases where parkinsonism is part of the clinical spectrum (Williams et al., 2005). In the same article, Williams points out that there is some overlap with the lysosomal storage disease Niemann-Pick disease type C (NPC). This observation, with the appropriate caveat that the L-DOPA responsiveness in Kufor-Rakeb differs from NPC, seems prescient now that the Kufor-Rakeb gene is cloned as a...  Read more

The important question when thinking about the exciting identification of ATP13A2 mutations by Ramirez and others is: is this Parkinson disease? The Kufor-Rakeb syndrome is reported to have many of the features of parkinsonian disorders, including bradykinesia and a response of the extrapyramidal signs to L-DOPA. However, the disease also has several other components that distinguish it from typical PD, such as spasticity, vertical gaze defects, as well as dementia. Some of these signs are so unusual that it has been suggested that the disease is regarded as nosologically distinct from PD, and put into a category with other rare inherited diseases where parkinsonism is part of the clinical spectrum (Williams et al., 2005). In the same article, Williams points out that there is some overlap with the lysosomal storage disease Niemann-Pick disease type C (NPC). This observation, with the appropriate caveat that the L-DOPA responsiveness in Kufor-Rakeb differs from NPC, seems prescient now that the Kufor-Rakeb gene is cloned as a lysosomal ATPase, ATP13A2, by Ramirez and colleagues.

Mutations turn out, perhaps unsurprisingly given the recessive inheritance of Kufor-Rakeb, to be fairly simple loss-of-function mutations. Although the wild-type protein is found in lysosomes, mutants are associated with ER and other compartments. Most likely, the mutant forms are degraded by ERAD (ER-associated degradation) or a similar process. Given that the mutations remove whole helixes, the protein will probably not fold correctly and will be degraded rather than mature for lysosomal function. This leads to the logical question: what is the function of wild-type ATP13A2 that is so critical for a number of neurons? As Ramirez et al. point out, the substrate specificity of ATP13A2 (or any other type 5 P-type ATPase) is unknown, but this is clearly the next piece of information required for understanding this disease.

So, given the clinical and molecular evidence to date, should we regard Kufor-Rakeb syndrome as (a) one of the lysosomal diseases that has parkinsonism as part of its spectrum or (b) a disease etiologically related to ”true” Parkinson disease. As has been discussed in other forums, this central question is a common one to many forms of recessively inherited diseases and is critical to our understanding of how (or whether) to place these types of genetic disorders in the same pathway as PD. An obvious way to help our classification would be to have autopsy material available from people carrying ATP13A2 mutations. This would allow us to ask obvious questions such as: is the pathology a synucleinopathy and therefore PD-like or a tauopathy and therefore PSP-like? Is there a myelination deficit? Is there evidence of lysosomal dysfunction and, if there is, is this also seen in sporadic PD? One of the very interesting pieces of data in the Ramirez paper is the observation of increased ATP13A2 expression in sporadic PD, although it is not quite clear how this relates to the loss-of-function pathogenic mutations. Unfortunately, autopsies for these rare recessive diseases, often found in remote kindreds, are rarely performed, so such questions, sadly, may remain open for some time.

View all comments by Mark Cookson

Ramirez et al. report the identification of mutations in a novel gene, ATP13A2, in Kufor-Rakeb syndrome, an autosomal recessive condition associated with pyramidal tract degeneration, dementia, and parkinsonism. Because of the prominent parkinsonian signs, the causative gene for this condition has been labeled PARK9. Based on prior linkage and analysis of a new family from Chile with this condition, and using a candidate gene approach, the authors have identified three types of mutations in ATP13A2. Although the mechanisms for each mutation are different, they all lead to truncation of the protein and loss of its localization to the lysosomal membrane. Thus, at first glance this appears to be a loss of function condition: it is autosomal recessive, and the mutations appear to lead to loss of function of the normal protein.

What could be the normal function of this protein? Based on its sequence homology and localization, this predominantly neuronal protein may function as a lysosomal ATPase, preserving the lysosomal pH gradient. Our previous studies had suggested that...  Read more

Ramirez et al. report the identification of mutations in a novel gene, ATP13A2, in Kufor-Rakeb syndrome, an autosomal recessive condition associated with pyramidal tract degeneration, dementia, and parkinsonism. Because of the prominent parkinsonian signs, the causative gene for this condition has been labeled PARK9. Based on prior linkage and analysis of a new family from Chile with this condition, and using a candidate gene approach, the authors have identified three types of mutations in ATP13A2. Although the mechanisms for each mutation are different, they all lead to truncation of the protein and loss of its localization to the lysosomal membrane. Thus, at first glance this appears to be a loss of function condition: it is autosomal recessive, and the mutations appear to lead to loss of function of the normal protein.

What could be the normal function of this protein? Based on its sequence homology and localization, this predominantly neuronal protein may function as a lysosomal ATPase, preserving the lysosomal pH gradient. Our previous studies had suggested that aberrant α-synuclein can impair lysosomal acidification (Stefanis et al., 2001), providing a common pathogenetic mechanism for parkinsonism based on loss of lysosomal function (Cuervo et al., 2004 and ARF related news story). However, somewhat at odds with this idea, the authors report that mRΝΑ expression of ATP13A2 is actually increased in sporadic Parkinson disease patients. It may be that this occurs as a compensatory response against some sort of lysosomal stressor. The authors argue also for the possibility of gain of function of the mutant forms, through aberrant localization, aggregation within the endoplasmic reticulum, and resultant proteasomal dysfunction. Although I believe that this interpretation is more speculative, it potentially links this new gene with the ubiquitin-proteasome pathway, which is extensively implicated in the context of Parkinson disease and neurodegeneration in general. Whatever the precise mechanism of the effects of ATP13A2 mutants on neuronal homeostasis, this novel discovery further implicates aberrant protein degradation in the pathogenesis of Parkinson disease and related disorders.

View all comments by Leonidas Stefanis