open access: Nature Reviews: Key Advances in Medicine

MOVEMENT DISORDERS IN 2011
Translating new research findings
into clinical practice
Christine Klein and Dimitri Krainc
The discovery of mutations that contribute to movement disorders
has facilitated the identification of converging pathways and novel
therapeutic targets. Successful translation of these research findings into
clinical practice will require identification of early markers of disease
progression, and recent research indicates that progress is being made in
this area.
Klein, C. & Krainc, D. Nat. Rev. Neurol. 8, 65–66 (2012); published online 20 December 2011;
doi:10.1038/nrneurol.2011.212
The prevalence of Parkinson disease (PD)
and other neurodegenerative disorders
is rapidly increasing worldwide and is
expected to double by 2030, 1 yet not a single
disease-modifying treatment exists for this
disorder. Thus, translation of research findings
into all aspects of clinical practice—that
is, diagnosis, monitoring and treatment—in
movement disorders is a high priority. One
of the major challenges of translational
research in movement disorders has been
the apparent lack of specific molecular targets
as platforms for drug development.
How ever, as highlighted by a number of
important studies published in 2011, the
emergence of various forms of genetic PD
has offered us an exciting opportunity to
identify such targets.
‘‘ Identification and monitoring
of the earliest disease stages
… is of great importance
Most mutations that have been linked
to PD and related synucleinopathies seem to
converge on lysosomal and mito chondrial
pathways, suggesting that disruptions of
these pathways have key roles in disease
pathogenesis. The importance of lysosomal
function in synucleinopathies was highlighted
in a recent study by Mazzulli and
colleagues that examined Gaucher disease,
a rare lysosomal storage disorder caused by
mutations in the glucocerebro sidase (GBA1)
gene. 2 ’’
Patients with Gaucher disease and
their relatives have an increased incidence of
PD, and patients with idiopathic PD have an
elevated prevalence of mutations in GBA1.
Interestingly, accumulated α-synuclein
interferes with trafficking of glucocerebrosidase
from the endo plasmic reticulum
to the Golgi apparatus, which in turn leads to
decreased glucocerebrosidase activity and
more accumulation of α-synuclein. The
bidirectional effects of α-synuclein and
glucocerebro sidase form a positive feedback
loop that, beyond a certain threshold, leads
to self-propagating disease.
The findings suggest that this molecular
pathway applies also to patients with idiopathic
PD or other synucleinopathies who
carry a normal GBA1 gene. The results indicate
that therapeutic targeting of mutated
or normal gluco cerebrosidase to lysosomes
would be expected to prevent or diminish
the formation of toxic α-synuclein oligomers
and break the vicious circle of α-synuclein
aggregation and toxicity. Importantly, these
findings were confirmed in human neurons
derived from induced pluripotent stem
cells, 2 which represent a major advance for
the modeling of neurodegenerative and
other diseases. 3
The importance of lysosomal pathways
in PD was further highlighted in two backto-back
publications by Vilarino-Guell
et al. 4 and Zimprich et al. 5 that described
a dominantly inherited mutation in the
vacuo lar protein sorting 35 (VPS35) gene as
a novel, albeit rare, cause of late-onset PD.
As a component of the retromer complex,
VPS35 sorts cargo from endosomes back to
the trans-Golgi network, and disruptions in
this pathway are expected to affect lysosomal
function. Intriguingly, both studies detected
the same VPS35 mutation (Asp620Asn), in
Swiss and Austrian kindreds, respectively,
and the same mutation was also recently
identified in a German pedigree. 6 When the
analyses were extended to additional families
from various ethnic backgrounds, both
initial studies confirmed the Asp620Asn
mutation in independent cases and found
two additional variants in the VPS35 gene. 4,5
On the basis of these studies, and previous
data showing that the retromer regulates
endosomal sorting of amyloid precursor
NEUROLOGY
protein in models of Alzheimer disease, it
will be interesting to examine the role of
VPS35 in the pathogenesis of PD. These
studies also highlight the importance of
next-generation sequencing for the discovery
of genetic factors—many of which
are likely to be rare—that cause or contribute
to complex movement disorders. 7
Besides improving our understanding of
disease biology, the identification of monogenic
forms of movement disorders has
opened up a new window into the pre motor
stage of neurodegenerative conditions—the
historical frontrunner being Huntington
disease—whereby individuals at risk can
be studied prospectively. Identification
and monitoring of the earliest disease
stages, during which treatment and neuroprotection
are expected to be most effective,
is of great importance. Selection of carefully
characterized and homogeneous cohorts of
patients or at-risk individuals will be vital
for the development of new drugs for PD
and other movement disorders. This task
would be greatly facilitated by employing
adequate biomarkers for diagnosis of the
disease, and for monitoring its course and
potential effects of treatment.
In a study published in PLoS ONE,
Yanamandra et al. hypothesized that autoimmune
reactivity towards specific proteins
and self-assembled complexes that
are involved in disease pathology may
serve as sensitive biomarkers of neurodegeneration.
8 The researchers measured
Key advances
■ α‑Synuclein and glucocerebrosidase
form a bidirectional pathogenic loop,
providing an important pathophysiological
mechanism in the development of
Parkinson disease (PD) 2
■ Next‑generation sequencing has led to
the discovery of a new gene (VPS35)
associated with late‑onset PD; this
finding implicates retrograde transport in
PD pathogenesis 4,5
■ α‑Synuclein‑reactive antibodies may
serve as a new biomarker for PD,
especially in its early phase 8
■ Induced pluripotent stem cell‑derived
neurons represent a patient‑specific
cellular model with great potential for
the study of disease biology 2
■ The first double‑blind, sham‑surgery‑
controlled, randomized trial of viral gene
transfer of glutamic acid decarboxylase
resulted in improved motor scores in
patients with PD, and the treatment
was not associated with severe
adverse events 9
KEY ADVANCES IN MEDICINE JANUARY 2012 | S57