Diana A. Olszewska

Genetics of Frontotemporal Dementia

Frontotemporal dementia (FTD) is the second most common cause of dementia following Alzheimer’s disease (AD). Between 20 and 50% of cases are familial. Mutations in MAPT, GRN and C9orf72 are found in 60% of familial FTD cases. C9orf72 mutations are the most common and account for 25%. Rarer mutations (<5%) occur in other genes such as VPC, CHMP2B, TARDP, FUS, ITM2B, TBK1 and TBP. The diagnosis is often challenging due to symptom overlap with AD and other conditions. We review the genetics, clinical presentations, neuroimaging, neuropathology, animal studies and therapeutic trials in FTD. We describe clinical scenarios including the original family with the tau stem loop mutation (+14) and also the recently discovered ‘missing tau’ mutation +15 that ‘closed the loop’ in 2015.

New Perception of Mitochondrial Regulatory Pathway in Parkinsonism - Ubiquitin, PINK1, and Parkin.

Mutations in PARK2, a gene encoding cytosolic E3 ubiquitin ligase parkin cause autosomal recessive Parkinsonism similar to mutations in the less prevalent PINK1 (PTEN induced putative kinase 1). Parkin and PINK 1 (Ser/Thr kinase) eliminate damaged mitochondria through mitophagy and mutations cause accumulation of impaired mitochondria and reactive oxygen species (1). PINK1, when activated by depolarization of the mitochondrial membrane potential, leads to phosphorylation and activation of E3 parkin ligase [Okatsu (2)]. PINK1 acts upstream to parkin accelerating latent E3 parkin activity and increasing accumulation of parkin on depolarized mitochondria in Drosophila. Presumably, PINK1-dependent phosphorylation of parkin at Ser65 accelerates E3 parkin activity. However, the substrate for PINK 1 phosphorylation of parkin has remained elusive. Koyano et al. (1) demonstrated that PINK1 phosphorylates ubiquitin, which subsequently activates parkin on damaged mitochondria. PINK1-dependent parkin activation proceeds in two phases: phosphorylation of ubiquitin-like (UBL) domain of parkin at Ser 65, followed by phosphorylation at Ser 65 of ubiquitin itself. While UBL domain is known for keeping parkin inactivated, phosphorylation of Ser 65 activates parkin partially (3). Autoubiquitination is not promoted by non-phosphorylated ubiquitin. Kane et al. (4) and Kazlauskaite et al. (3) also confirmed phosphorylated ubiquitin as a parkin activator. These studies shed light on two further PINK1/parkin metabolism issues: (1) why does a phosphorylation-deficient mutation of parkin inhibit formation of a ubiquitin-ester (an intermediate product in the parkin activation pathway), (2) why does a phosphomimetic parkin mutant still require PINK1 for activation. Koyano et al. used phosphate affinity (phos-tag) PAGE assay to identify a slower-migrating ubiquitin band, phosphorylated by PINK1 on damaged mitochondria (i.e., pre-treated a protonophore). Mass spectrometry analysis identified Ser 65 as the ubiquitin phosphorylation site. A yeast system was used to confirm that phosphorylated ubiquitin at Ser 65 is a parkin activator. Thus, ubiquitin acts not only as a substrate for phosphorylation but also activates parkin itself. Koyano et al. proposed that parkin is fully activated by repression of the catalytic cysteine by RING0 domain unlocked by phosphorylated ubiquitin and UBL domain. Parkinson’s disease is an incurable neurodegenerative condition. Defects in mitochondrial regulation have been implicated as one of the key elements in the etiology of parkinsonism. PINK 1 and parkin act as neuroprotective agents by maintaining mitochondrial homeostasis. Decreased antioxidant effect may be seen in other serious disorders, such as tumors where parkin expression is frequently diminished (5). Mechanism of interaction between these two proteins has been unclear. Koyano et al. used a yeast system to aid demonstration of the important role of phosphorylated ubiquitin acting as a long-searched for mediator between PINK1 and parkin. The above results may lead to novel therapeutic options for Parkinson’s disease. Cornelissen et al. (6) proposed a treatment strategy based upon inhibition of ubiquitin-specific protease 15 (USP15), a deubiquitinating enzyme (DUB) counteracting Parkin-mediated autophagy, while Kazlauskaite et al. (3) suggested development of a parkin activator in the form of ubiquitin-like agent. PINK1 driven phosphorylation of ubiquitin has important implications in understanding the underlying pathophysiological mechanisms of parkinsonism and to develop new treatment strategies for an incurable movement disorder.

Psychiatric symptoms in preclinical behavioural-variant frontotemporal dementia in MAPT mutation carriers

Objective To characterise psychiatric symptoms in preclinical and early behavioural-variant frontotemporal dementia (bvFTD), a neurodegenerative disorder whose symptoms overlap with and are often mistaken for psychiatric illness. Methods The present study reports findings from a systematic, global, prospective evaluation of psychiatric symptoms in 12 preclinical carriers of pathogenic MAPT mutations, not yet meeting bvFTD diagnostic criteria, and 46 familial non-carrier controls. Current psychiatric symptoms, informant-reported symptoms and lifetime prevalence of psychiatric disorders were assessed with The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and the Neuropsychiatric Inventory Questionnaire. Fisher exact test was used to compare carriers and non-carriers’ lifetime prevalence of six DSM-IV disorders: major depressive disorder, panic attacks, alcohol abuse, generalised anxiety disorder, panic disorder, and depressive disorder not otherwise specified. Other DSM-IV disorders had insufficient prevalence across our sample for between-group comparisons, but are reported. Results Non-carriers had greater prevalence of mood and anxiety disorders than has been reported for a general reference population. Preclinical carriers had lower lifetime prevalence of mood and anxiety disorders than non-carriers, except for depressive disorder not otherwise specified, an atypical syndrome comprising clinically significant depressive symptoms which fail to meet criteria for major depressive disorder. Conclusion Findings suggest that early psychiatric symptoms of emergent bvFTD may manifest as emotional blunting or mood changes not cleanly conforming to criteria for a DSM-defined mood disorder.

SCA 6 with Writer's Cramp: The Phenotype Expanded

Spinocerebellar ataxia type 6 (SCA6) presents typically with a pure cerebellar syndrome. Only 1 SCA 6 patient with writers cramp has been reported on and a family history of ataxia and writers cramp has never been reported on. Two other SCA6 patients with a shoulder girdle/hand dystonia and unspecified upper‐limb dystonia with a family history of ataxia have been reported on. We report on the largest family with SCA6 and writers cramp. The proband developed dysarthria, ataxia, and writers cramp by age 37. His father presented with ataxia at 55, followed by writers cramp and dysarthria. The probands brother developed ataxia at 41, followed by dysarthria and writers cramp. A paternal uncle (deceased; not examined) and 58‐yr‐old brother both developed pure ataxia (genetic testing is pending). This large family with complex movement disorder demonstrates that it is important to consider SCA6 in a patient presenting with an ataxia and writers cramp and supports cerebellum involvement in dystonia.

PINK1, parkin, and autophagy receptors: A new model of mitophagy

Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and parkin mutations cause autosomal recessive Parkinson’s disease (PD) associated with mitochondrial dysfunction. PINK1, a serine/threonine-protein kinase, phosphorylates ubiquitin and the ubiquitin-like domain of parkin. Damaged mitochondria acquire ubiquitin chains bound by two autophagy receptors (optineurin [OPTN] and p62) and are discarded via mitophagy. PINK1 and parkin mutations disrupt this process, and autophagy receptors mutations cause neurodegeneration. However, the precise function of autophagy receptors remains unclear, and their role in cellular “waste management” could have therapeutic implications for neurodegeneration. Lazarou and colleagues describe a new mitophagy model in Henrietta Lacks (HeLa) cells where parkin is not expressed. They developed HeLa cells without autophagy receptors and then induced mitochondrial damage. The damaged mitochondria were not discarded, but mitophagy occurred in wild-type cells indicating that mitophagy requires autophagy receptors. They then re-expressed all autophagy receptors, and each of the re-expressed receptors translocated to mitochondria. However, mitophagy was only rescued by OPTN and another autophagy receptor called nuclear dot protein 52kDa (NDP52). Moreover, the presence of both OPTN and NDP52 was mandatory for mitophagy to occur, except mitophagy was possible with OPTN alone in the presence of an upstream autophagy regulator called TANK binding kinase 1 (TBK1). Furthermore, the authors showed that although parkin amplifies mitophagy, its presence is not mandatory for the process to go ahead. OPTN and NDP52 can activate mitophagy independently of parkin, but their recruitment requires PINK1 kinase. Moreover, the authors demonstrated the OPTN mutation (E50K) increased TBK1 and OPTN binding, resulting in OPTN phosphorylation by TBK1 and improved mitophagy in the absence of parkin. Enhancing mitophagy might be an interesting therapeutic approach for neurodegeneration. Parkin is thought to be central to the mitophagy process. However, recent studies showed that PINK1 enables the autophagosome engulfment by dividing larger particles (too large to enter the autophagosome) into the smaller packages, thus speeding up mitophagy. PINK1 has other substrates or roles independent of parkin and was recently named “a master mitophagic regulator” in coordinating, sorting, and managing damaged mitochondria. Lazarou and colleagues provide an exciting model where OPTN and NDP52, but not p62, act independently of parkin to activate mitophagy for “cell housekeeping.” This study will increase the focus on PINK1 as an activator of OPTN and NDP52 and guardian of the mitochondrial garbage disposal system. It may lead to a development of NDP52 and OPTN enhancers as therapeutic options in PD.

MUL1-A new potential for a therapeutic target for Parkinson's disease a commentary on "MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin" by Yun and colleagues (eLife 2014; 3: 1-26).

Mitochondrial dysfunction, impaired protein degradation, oxidative damage, and impaired mitophagy all have important roles in the pathogenesis of Parkinson’s disease (PD). Familial PD studies advanced our understanding of PD pathogenesis. For example, mutations in relevant genes PINK1 (PTEN-induced putative kinase) and parkin cause autosomal recessive young-onset PD; PINK1 activates Parkin (E3-ubiquitin ligase), which then phosphorylates ubiquitin, leading to the elimination of damaged mitochondria (mitophagy). PINK1 and parkin mutations disrupt this pathway, and parkin enhancement is a proposed therapeutic approach in PD. In mice, loss of PINK1 and parkin results only in subtle PD signs, unlike in humans where levodoparesponsive parkinsonism develops. Intriguingly, 1 patient with parkin homozygous mutation and confirmed functional parkin loss surprisingly did not develop PD even by age 66. Furthermore, ubiquitination of fusion mediator-mitofusin (mfn2; part of the mitochondrial network and mitophagy cascade), was impaired in this patient, and there was no observed compensation for the impaired mfn2 ubiquitination. This suggests the existence of other compensatory proteins or pathways that may prove useful for PD therapeutics. Yun and colleagues identified a novel ligase that rescues the defects caused by mutations in PINK1 and parkin mutations in Drosophila called MUL1 (Mitochondrial E3-Ubiquitin Protein Ligase 1). MUL1 guards mitochondrial homeostasis and promotes fragmentation of mitochondria by stabilizing dynamin-related protein (drp1) or degrading mitofusin (mfn). It is not known if increased mfn/decreased drp1 alone causes mutant phenotypes. MUL1 seems to act in parallel with PINK1 and parkin. Loss of PINK1 or parkin combined with additional loss of MUL1 results in exaggerated mitochondrial damage and more severe PD phenotype in flies when compared with loss of PINK1 or parkin alone. When MUL1 is absent, any compensation for PINK1 or parkin defects is impossible. Moreover, decreased mfn ubiquitination with an exaggerated phenotype as a result of the loss of both MUL1 and parkin was confirmed in mouse cortical neurons. MUL1 upregulation rescues mitochondrial damage caused by PINK1 or parkin deficit, and ligase activity is crucial for this rescue. Yun and colleagues demonstrated that mitofusin overexpression, but not dynamin-related protein loss, results in mutant phenotypes in Drosophila and mice. MUL1 and parkin can rescue the PINK1 mutants independently. This paper highlights that new PD-targeted therapeutic possibilities involving MUL1 are promising. Moreover, other studies reported MUL1 involvement in regulation of seleniteinduced mitophagy. Selenite at low doses is known to induce mitophagy. Again, ligase activity is crucial for this process. Selenium role as a chemoprotective agent should be investigated further, and other agents capable of MUL1 upregulation should be sought. In conclusion, the MUL1 pathway may be an important covariable in PINK1 and parkin mutation carriers. Furthermore, MUL1 forms a complex with VPS35, a candidate gene in Mendelian PD, and mutations in MUL1 should be sought for in familial PD.

Novel gene (TMEM230) linked to Parkinson’s disease

Mutations in six genes are known to cause Parkinson’s disease (PD) (autosomal dominant: alpha-synuclein, LRRK2, VPS35 and autosomal recessive: Parkin, PINK1 and DJ1) and number of other genes are implicated. In a recent article Deng and colleagues studied a large four generation American family of European descent and linked mutations in a novel gene, transmembrane-protein 230 gene (TMEM230) with lewy body confirmed PD. The authors demonstrated that pathogenic TMEM230 variants in primary mouse neurons affected movement of synaptic vesicles suggesting that TMEM230 may slow vesicular transport. Further experiments in HEK293 cells (carrying the pathogenic TMEM230 variants) showed increased alpha-synuclein levels. This study indicated that the impaired vesicular trafficking may contribute to the pathogenesis of PD. Understanding the various cellular mechanisms leading to PD may lead to the development of novel, much needed therapeutic options. These mechanisms could include: enhanced clearance of damaged mitochondria, development of kinase inhibitors, VPS35/retromer function enhancers or now the possibility of vesicular transport modification.

Speech myoclonus due to probable pregabalin adverse drug-reaction

Myoclonus, an involuntarymuscle jerk is a brief, sudden, muscle contraction (positive myoclonus) or interruption of a muscle activity (negative myoclonus) [1]. Acute-onset myoclonus should prompt a search for medication adjustments or an adverse drug-event. Benzodiazepines, antidepressants, lithium, opioids, calcium channel blockers and anticonvulsants can all trigger myoclonus [1]. Pregabalin is an antiepileptic (AED) used in neuropathic pain, a derivative of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which does not bind to GABA or benzodiazepine receptors. Pregabalin binds to a subunit of voltage-gated calcium channels (alpha2-delta site) [2] and probably modulates neurotransmitters release. Pregabalin-induced myoclonus is rare, in 1/ 100e1/1000 [3]. Pregabalin may accumulate in chronic kidney disease (CKD) as it is almost exclusively excreted by the kidneys [2]. A minimal amount of pregabalin is metabolised by liver, with little effect on the cytochrome P450 system and so drug interactions are less likely [2]. While patients on hemodialysis may need increased doses, there are no data regarding peritoneal dialysis [4]. A Pregabalin induced adverse drug-event has been reported in three patients on hemodialysis [6] and in one on peritoneal dialysis [5]. We report a probable adverse drug-reaction due to pregabalin in a patient on peritoneal dialysis manifesting as a prominent myoclonus affecting speech. A 66year-old manwith CKD on home peritoneal dialysis for 10 months was admitted with a five days history of gait ataxia and light-headedness. He had proliferative glomerulonephritis, hypertension, and gout. Urea was 31 mmol/L and creatinine 509 umol/L (creatinine clearance was unchanged at 13.4 ml/min). Full blood count, glucose, liver function tests, thyroid function tests, vitamin B12, folate, c-reactive protein and aluminium were normal. Magnetic resonance imaging (MRI) showed microvascular ischaemia in the brain and minor spondylotic changes in the cervical spine. Medications included pregabalin, allopurinol, aspirin, furosemide, doxazosin, alfacalcidiol, sevelamer carbonate, atorvastatin, esomeprazole, calcium acetate and amlodipine. Pregabalin 50 mg once a day had been prescribed for paraesthesiae six months previously and had been increased to 75 mg once a e months pre-admission. The last dose of pregabalin was r to admission. He had no history of confusion, loss of consciousness or hallucinations. He was seen by a neurologist and examination revealed multifocal myoclonus affecting jaw, tongue and limbs with a dramatic effect on speech [video]. Positive, action myoclonus occurred when speaking or during any movement of the lower facial muscles involved in jaw opening and tongue movements. Negative myoclonus was present with posture-holding of arms and legs when outstretched but not at rest [video]. There was no palatal myoclonus. Myoclonus whilst swallowing was not assessed. Myoclonus was spontaneous and not stimulus-sensitive (startle, noise, touch). the gait was wide-based.

Lysosomal Storage Disorders and Parkinson's Disease: New Susceptibility Loci Identified: Lysosome and PD: An Update

Mutations in the glucocerebrosidase gene (GBA) cause autosomal recessive Gaucher’s disease. The connection between the GBA gene and Parkinson’s disease (PD) was recently recognized; GBA mutations impair alpha-synuclein clearance, and prompt a search for any relationship between PD and other lysosomal disorders (LSDs). Mutations in alpha-synuclein, LRRK2, VPS35, PINK1, DJ1 are associated with mitochondrial and endo-lysosomal dysfunction. Both mitochondria and lysosomes are involved in lipid and protein trafficking and metabolism. Moreover, mutations in LSD genes may lead to PD by altering lysosomal activity resulting in alpha-synuclein accumulation and disrupting the transport of highly specific hydrolases within dopaminergic neurons, thus impairing mitochondrial quality control mechanisms. Homozygous and heterozygous GBA mutations are the largest genetic risk factor for PD (5-20 increased risk). While there are multiple studies involving GBA in PD, there are few studies of other lysosomal disorders. The small number of studies of other LSDs may be because patients with severe childhood LSDs die before PD symptoms appear, or that once PD is diagnosed metabolic tests are not done, resulting in few patients available for study. However, features of parkinsonism occur in some metabolic disorders, including Niemann Pick’s disease, lipogranulomatosis, or ceroid lipofuscinosis. Robak and colleagues recently assessed the mutation burden of other LSD genes and PD susceptibility by using the largest available whole exome sequencing (WES) database (1156 PD patients and 1679 controls). The results were replicated in two independent cohorts (PPMI and NeuroX) of over 7000 PD patients and more than 6000 controls. Fifty-four lysosomal genes were evaluated. The authors confirmed the known PD association at the Gaucher’s and Niemann Pick’s loci. They also showed association of three novel loci including cathepsin D gene (CTSD) associated with ceroid lipofuscinosis (seizures, myoclonus, ataxia, blindness), solute carrier family 17 member 5 (SLC17A5) associated with Salla disease (developmental delay, seizures, ataxia, spasticity, athetosis), and N-acylsphingosine amidohydrolase (ASAH1) associated with Farber lipogranulomatosis (subcutaneous nodules, deformed joints, hoarseness) with PD. Over half of PD patients had at least one mutation in a LSD gene. Roughly one-fifth carried multiple mutations. Thus, the susceptibility to PD increased in the presence of several lysosomal genetic risk factors. Importantly, the association remained significant even following GBA exclusion. The three novel risk factors identified by Robak et al. have a role in lysosomal transport (SLC17A5), ceramide metabolism (ASAH1), and in alpha-synuclein degradation (CTSD is a lysosomal proteinase). In the near future, we are hopeful that explicit diseasemodifying therapies will be developed for specific genetic forms of PD such as LRRK2 kinase inhibitors, knockdown therapy for SNCA duplications, parkin mitochondrial enhancers, or enzymatic compounds capable of crossing brain-blood barrier in GBA carriers (such as over the counter medication for respiratory conditions facilitating lysosomal exocitosis-ambroxol). The additional loci discovered in this study and the identification of an increased burden of lysosomal genetic risk factors in PD may increase our understanding of the interplay between mitochondria and lysosomes (two closely related cell housekeeping regulators), and provide further insight into PD pathogenesis. Thus hopefully leading to the development of innovative precision therapies for PD.

Reversible Corticobasal Syndrome due to Coeliac Disease: Reversible Cbs Due To Coeliac Disease

Coeliac disease (CD) can present with cerebellar ataxia, peripheral neuropathy, gluten encephalopathy, epilepsy with occipital calcifications, and (rarely) ataxia with cortical myoclonus. Myoclonic ataxia is often associated with refractory CD. The myoclonus is cortical and often progressive. We describe a woman with coeliac disease, myoclonic ataxia, and corticobasal syndrome (CBS) with alien limb phenomenon that resolved with immunosuppression.