Posted in Journal Reviews on 19th Sep 2013
Parkin mutations should be considered in early–onset parkinsonism. They are the most common cause of autosomal recessive familial PD cases, and also account for 15% of sporadic cases in the under-45 age group. The parkin gene plays an important role in mitochondrial quality control and the ubiquitin proteasome system.
Doherty and colleagues describe the clinicopathological features of 5 unrelated patients with parkin disease and compared them with 5 pathologically confirmed PD cases and 4 control subjects. The parkin and PD patients were matched for both disease duration and age of death.
Consistent with previous reports, the presenting features of the parkin disease patients were hand or leg tremor, often associated with dystonia and gait abnormalities. The patients’ disease followed a slowly progressive course and responded well to levodopa, but all developed motor fluctuations. Perhaps reassuringly for patients with this mutation, there was a dearth of cognitive and neuropsychiatric features in these cases, despite the long disease duration (range 27-50 years).The authors speculate that this may be explained by the sparing of the nucleus basalis of Meynert and the cortex.
As well as being phenotypically distinct from the PD cases, parkin cases were pathologically defined by relative preservation of the dorsal tier of the substantia nigra with sparse or no Lewy bodies. This is in contrast with the brain bank studies of typical clinical PD which invariably predicts Lewy pathology. As larger pathological studies of genetic PD patients are done in future, they may be expected to yield further insights into the complex cellular mechanisms of genetic Parkinson’s disease, with the hope that this will eventually translate into therapeutic advancements.- GC
Doherty KM, Silveira-Moriyama L, Parkkinen L et al.
Parkin disease: a clinicopathologic entity?
JAMA Neurol. 2013 May 1;70(5):571-9 doi: 10.1001/jamaneurol.2013.172
Riding the CREST of the ALS genetic wave
The Gitler lab have just identified 25 new genes potentially linked with ALS. The technique of exome sequencing was at the heart of their approach -a high throughput technology focusing on the exons alone, looking for mutations that effectively alter the amino acid sequence of genes. By looking at apparently sporadic cases in which both parents were still alive and from whom DNA was also available they looked specifically for genetic variations that were present in the affected individuals, but not in the parents i.e. de novo mutations. The discovery of 25 mutations in 47 cases is striking, all the more so because of the concentration of genes involved in chromatin regulation. One gene, SS18L1 (or CREST), is of particular note as the team did indeed fInd a further mutation on screening a cohort of 62 familial ALS index cases. Determining the wider significance of this and other variations requires large scale screening in ALS cohorts. It is also important to note that the cases in the trios studied were all remarkably young (mean age less than 40y), which is somewhat atypical, but might suggest that strong genetic factors may underly their disease. CREST is implicated in neurite outgrowth and in vitro studies suggested that the mutant forms of CREST impaired activity dependent dentritic outgrowth. However, the functional data the team present leaves out some details, including the reasoning for their use of a mouse construct rather than a human construct for the truncation mutation, and the apparent use of a human construct to model the missense mutation.Furthermore, their dendritic images may suggest dendritic degeneration rather than aberrant branching (which is still, nevertheless, interesting). More interesting is the interaction they seem to find between CREST and FUS, a major ALS gene that causes a predominantly lower motor neuron phenotype. We hope to hear further developments on this front soon.- JS
Chesi et al.
Exome sequencing to identify de novo mutations in sporadic ALS trios.
NATURE NEUROSCIENCE 16, 851–855 (2013)
A nosey solution?
For many years injectable therapies were the main stay for the treatment of relapsing remitting multiple sclerosis (MS). More recently novel oral and intravenous therapies have become available. This animal study by Duchi et al. investigated the efficacy of nasal drug administration as a new, non-invasive treatment delivery strategy in MS. Mice with experimental autoimmune encephalomyelitis (EAE) were administered Glatiramer acetate (GA), Cannabidiol (CBD) or prednisolone by different routes. Specifically, subcutaneous and nasal administration, with and without the nasal delivery system (NDS), were compared. Differences between groups were measured using clinical scores and levels of inflammatory cytokine expression. Clinical scoring was carried out twice daily for 26 days following EAE immunisation by two different observers. Prednisolone was administered on the same day as disease inoculation (preventative) while the other treatments were introduced on the day the first clinical sign appeared (acute). After 26 days, there was a significant reduction (39%) in clinical disease signs following nasal administration of GA via the NDS, as compared to the subcutaneous injection (6.5%) of the same drug and dose (6.7mg/kg/day).This suggested high efficacy of the NDS in the mouse model. There was also suppressed expression of both cytokines tested (IL-6 and TNF-alpha) in the cerebellar tissue of the GA NDS group. Nasal GA via the NDS significantly suppressed the histopathological outcome of disease compared to untreated (control) EAE mice.
The same dose of GA given nasally as an aqueous solution was ineffective in reducing clinical disease signs or suppressing cytokine expression in EAE mice and caused more inflammation of the nasal mucosa than GA administered via the NDS.The combination of GA and CBD via the NDS showed increased suppression of clinical signs when compared to either drug alone,indicating that the addition of an anti-inflammatory drug, such as CBD, could improve treatment. This combination also augmented neuronal proliferation in the hippocampus compared to untreated EAE mice. Prednisolone administered via the NDS showed a significant reduction (79.6%) in clinical scores while the same dose given subcutaneously had no effect (0% reduction). Prednisolone via the NDS also appeared to delay the development of disease, as the first clinical signs in this group appeared on day 15 compared to day 10 in the untreated mice. Lower inflammatory cytokine mRNA expression and improved histological disease manifestations were also noted in this group.
While this is a preliminary study, it offers support for the efficacy of the nasal delivery system in the administration of Glatiramer acetate,Cannabidiol and prednisolone,which may in the future translate to use in humans for the treatment of MS. There are many possible benefits of nasal drug administration including; improved compliance, non-invasiveness, and use in needle-phobic or dysphagic patients. The use of appropriate intranasal administration techniques (mice in the study were lightly anesthetised to avoid sneezing!) and the effect of repetitive/ long-term dosing on the nasal mucosa are areas requiring additional consideration in the future. Further research is warranted to continue to explore this alternative treatment strategy.- HB
Duchi S, Ovadia H and Touitou E.
Nasal administration of drugs as a new non.invasive strategy for efficient treatment of multiple sclerosis.
J NEUROIMMUNOL 2013; 258:32-40.
Panel of reviewers
GC – Gemma Cummins, Van Geest Centre for Brain Repair, Cambridge University.
JS – Jemeen Sreedharan, Dept of Neurobiology/ Neurology, University of Massachusetts Medical School, Worcester, US.
HB – Heidi Beadnall, Royal Price Alfred Hospital/Brain Mind and Research Institute,Sydney, Australia
ACNR 2013; 13:4:38