In the two decades since the first causative gene for
Parkinson’s disease (PD) was discovered, there has been a gradual but
inevitable change in the scientific understanding of PD as a hereditary
disorder. Cumulative genetic discoveries have helped paint a new picture of the
disease and uncover novel pathways that may finally provide an explanation for
the progressive neuronal degeneration associated with PD, which remains one of
the mysteries of medical science. The emerging picture is causing many in the
field to rethink longstanding ideas about PD.
Of particular interest is the role of autophagy, a fundamental
physiological process for recycling cellular waste that is the subject of the
recently announced 2016
Nobel Prize in Physiology or Medicine. Revelations from research on known PD
genes have established autophagy malfunction as one of the leading theories on what
goes wrong to cause the characteristic motor and other symptoms of the disease.
Redefining Parkinson’s Disease
PD used to be thought of as the prototypical sporadic disease–the
genetic links were weak and no other cause was evident. While there is still no
well-established cause, it is now clear that genetic factors play a significant
role in the overall burden of the disease, not just in well-defined “pure” genetic
forms, but in the much larger population with sporadic disease.
“For 20 years, the tide has been going out on the idea that
genetics does not play a part in Parkinson’s disease,” says John Hardy, Ph.D., a
molecular biologist at University College London and a leading researcher in
the genetics of Parkinson’s. Each year more genetic risk factors were found, he
says, even as the rate of new genetic findings relevant to the disease dropped
off in the last decade.
“Genetics always plays a part,” Hardy says emphatically. “I
doubt there are any cases where there is no genetic predisposition.”
Hardy stops short of calling PD a “primarily genetic
disorder,” as other
researchers have. Genetics alone does not explain every case, he says; unknown
environmental factors and just plain chance also play roles. He points to a pair
of 72-year-old identical twins his research group studied, one of whom had
Parkinson’s for 15 years. The sister, whose genome was exactly the same, was
without symptoms. “It’s obviously a bit more complicated than just saying
genetics is destiny,” Hardy says.
M.D., a Parkinson’s researcher at the University of Toronto and member of
the Dana Alliance for Brain
Initiatives, says it’s still not clear to what extent genetic factors are contributing
to sporadic PD. “Most people believe that there probably is an important
genetic component. In some cases, it is very strong and probably sufficient to
cause the disease, while in other cases, it may be that the genes act in combination
with environmental factors. There may also be protective genes that we haven’t
The genetics of PD is complicated because there are two
levels of genetic relevance: genes that are causative and genes that increase
risk. Pure genetic forms of the disease are caused by the inheritance of a
single gene from one parent (in autosomal dominant forms) or both parents (in
autosomal recessive forms). There are a number of well-established, albeit
rare, monogenic forms of Parkinson’s. Synuclein
(SNCA/PARK1/4) was the first PD gene discovered, in 1996. The second, dardarin (LRRK2), is the most frequent
known cause of late-onset PD. A gene called parkin
(PARK2) is the most common autosomal recessive cause. Altogether, the dozen or
so known causative genes account for roughly 30 percent of familial cases of
the disease, and an estimated 3 percent of all PD cases.
The vast majority of people with PD–at least 90 percent of
cases–have no known family history of the disease, making these so-called
sporadic cases the largest population by far. Sorting out the genetic
contribution to sporadic disease is a puzzle whose pieces have come together
bit by bit from the accumulated data of 20 years of genetic studies. These
include twin studies; gene linkage studies, which analyze families with
multiple cases; genome-wide association studies, which compare large swaths of
the population with patient groups; and most recently, whole genome sequencing.
Dozens of chromosomal “regions of interest” have been
uncovered using these tools of modern genomic science. It’s quite clear, says
Hardy, that “even sporadic disease has genetic predisposition, and we’re now understanding
Risk-conferring genes are not sufficient in and of themselves
to cause the disease; rather, they increase one’s likelihood of developing PD.
The degree to which risk increases for any one individual carrying any one risk-conferring
gene is impossible to say, but Hardy estimates it may bump one’s chances of
developing Parkinson’s three- to five-fold.
There also may be an additive effect of risk genes: the more
an individual has, the greater the likelihood of developing disease. Genes that
act on similar pathways–for example, different aspects of autophagy–could have
a cumulative effect that is greater than each individual gene, and genes that
act on different pathways altogether could, in theory, have a synergistic
The Autophagy Links
Mutations in a gene called GBA are so far the most common
genetic abnormality found in PD patients. GBA encodes glucocerebrosidase, a
housekeeping enzyme used by lysosomes–a critical piece of the autophagy
machinery built into every cell. Lysosome organelles act like recycling centers
for the cell, collecting and processing cellular garbage, toxins, and bacteria.
When lysosomes malfunction, cellular junk can build up. GBA mutations cause the
most common lysosomal storage disorder (Gaucher’s disease), and the gene’s involvement
in parkinsonism was discovered because so many relatives of people with
Gaucher’s disease develop PD symptoms.
Yet GBA is just a small piece of the genetic puzzle of PD. Genome
studies keep pulling up more candidate risk-conferring genes and regions of
interest, complicating the puzzle more than completing it. Many of these mutations
also interfere with the autophagic system in one way or another. LRRK2, for
example, is emerging as a kind of “master regulator” of autophagy, Hardy says,
and there is some evidence to suggest that if a person carries both LRRK2 and
GBA, risk of PD increases. Lang says other recent
research suggests that GBA mutations raise disease risk in association with
a range of other known causative genes as well.
“Probably the newest development in terms of genetics and
how genetics has had an impact on our understanding of the pathogenesis of PD is
the expansion to another cellular mechanism, autophagy and lysosomal function,
that hadn’t been appreciated previously,” says Lang.
Roadmap for Earlier Diagnosis
A major goal driving genetic research are the twin needs for
earlier diagnosis and disease-modifying treatments. Like other
neurodegenerative diseases, the disease processes underlying PD are likely to
start years before the characteristic symptoms are obvious–as many as 15 years
in the case of PD. The earlier the diagnosis, the greater the chance that
therapeutic intervention can make a difference. Studying causative and
candidate genes to understand the functions of the disrupted gene products reveals
clues to the underlying pathophysiology of the disease, which eventually will
lead to biomarkers to aid early diagnosis as well as to new targets for drug
treatment. At least, that is the hope.
Already, Lang says, there are drugs in early developmental
stages that are based on new understandings garnered from the study of the GBA
and LRRK2 gene products. Clinical trials of investigational drugs are
complicated by the fact that what we call Parkinson’s is most likely a
heterogenous group of disparate disorders with different causes. This is
evident in the fact that the pure genetic forms of the disease have widely
varying ages of onset and rates of progression.
That fact also complicates early diagnosis, but even there,
progress is evident. “Genetic information is already helping diagnose
Parkinson’s disease,” says Hardy. He points to a recent study
by National Institute on Aging neurogeneticist Mike Nalls, Ph.D., and
colleagues that demonstrated the feasibility to predict who is likely to
develop PD based on a combination of genetic data and clinical testing,
including a smell test to screen for olfactory malfunction, an early marker of
The study lays out a potential roadmap for early
identification that might look like this: You go in to a clinic at age 55 or 60
for an annual checkup. They do a smell test as an initial screen. If that shows
olfactory impairment, you go for a whole-genome analysis that searches for
known PD-related mutations. If that indicates you’re at high risk, perhaps you
go for a brain scan that measures dopamine, the major neurotransmitter
implicated in Parkinson’s, and so on.
Hardy says a similar process is close to being actualized to
identify early Alzheimer’s. As scientific understanding of the spectrum of risk
genes increases, the accuracy of predictions will get better.
While this may well be the clinical norm once
"neuroprotective" or disease-modifying therapies are available, Lang
cautions that right now this type of approach can only be justified as part of
research efforts in defining people at the very earliest stages of the disease.
Hardy believes this kind of pathway might develop across the
board for such relatively common late-onset diseases as PD and Alzheimer’s
disease, if we understand enough about the genetics and we’ve got reliable markers
of early change. “Putting those things together should make it possible to
identify people right at the beginning of the disease process,” Hardy says. “We
think that is going to be the key to effective therapy.”