Antibody therapy in neurodegenerative disease

Advances in medical science have led to increased life expectancy and increased median age in the population. Because the symptoms of neurodegenerative diseases generally onset in mid- to late-life, a concomitant increase in the number of persons afflicted with these devastating diseases has occurred. Developing therapies for neurodegenerative diseases is of the highest priority due to the enormous cost of medical care required, as well as for the human suffering involved. Although caused by a variety of genetic and environmental insults, such diseases share commonalities. Many of these diseases are proteinopathies--diseases caused by misfolded, aggregating proteins. Antibodies that can recognize and remove misfolded proteins are ideally suited for proteinopathy therapeutics. The numerous intriguing advances in antibody-based therapies for neurodegenerative diseases are discussed in this review.     

Somatic gene therapy for a neurodegenerative disease using microencapsulated recombinant cells

Neurodegenerative diseases caused by lysosomal enzyme deficiencies are catastrophic illnesses with both peripheral organ and central nervous system abnormalities. The mucopolysaccharidosis type VII mouse with beta-glucuronidase deficiency was used to develop an alternate approach to gene therapy, in which a "universal" cell line engineered to secrete the missing enzyme is implanted directly into all recipients requiring the same enzyme replacement. The cells, though nonautologous, were rendered immunologically tolerable by protection in immunoisolating microcapsules. Since the blood-brain barrier impedes the passage of large molecules such as beta-glucuronidase, encapsulated cells producing beta-glucuronidase were introduced directly into the lateral ventricles of the brain. Based on this strategy, beta-glucuronidase was delivered throughout most of the central nervous system, reversing the histological pathology and reducing the previously elevated levels of lysosomal enzymes beta-hexosaminidase and alpha-galactosidase. The effectiveness of this approach was further demonstrated with improvements in the mutant circadian rhythm behavioral abnormalities. Compared to wild-type and heterozygous mice, the mutant mice had an unstable periodicity, fragmented activity, and a sixfold reduction in wheel running activity. After treatment, the mutant behavioral abnormalities were significantly improved with a more stable periodicity and a less fragmented pattern of activity. While the overall total activity level did not increase in the treated mutants, it did not show the deterioration observed in the sham-treated as well as in the untreated mutant mice. Hence, this alternative cell-based gene therapy demonstrates biochemical, histological, and behavioral efficacy and provides a potentially cost-effective and nonviral treatment applicable to all lysosomal storage diseases with neurological deficits.     

Olfactory dysfunction as a predictor of neurodegenerative disease

Olfactory dysfunction is present in patients diagnosed with Alzheimer’s disease or idiopathic Parkinson’s disease and can differentiate each of these disorders from related disorders with similar clinical presentations. The pathologic hallmarks of each disease are present in brain regions involved in processing olfactory input. Both the olfactory functional deficits and the corroborating pathologic lesions are present in asymptomatic subjects with increased risk of developing these diseases. Preclinical detection of neurodegenerative diseases is necessary to control their devastating effects on individuals and societies. We address whether olfactory dysfunction can be used to assess risk for developing Alzheimer’s disease or Parkinson’s disease in asymptomatic individuals. We argue that further characterization and a deeper understanding of olfactory deficits in these neurodegenerative diseases at the molecular, cellular, and systems levels will augment our acumen for preclinical detection and elucidate pathogenic mechanisms to guide the development of new therapeutic modalities.     

Olfactory dysfunction as a predictor of neurodegenerative disease

Olfactory dysfunction is present in patients diagnosed with Alzheimer's disease or idiopathic Parkinson's disease and can differentiate each of these disorders from related disorders with similar clinical presentations. The pathologic hallmarks of each disease are present in brain regions involved in processing olfactory input. Both the olfactory functional deficits and the corroborating pathologic lesions are present in asymptomatic subjects with increased risk of developing these diseases. Preclinical detection of neurodegenerative diseases is necessary to control their devastating effects on individuals and societies. We address whether olfactory dysfunction can be used to assess risk for developing Alzheimer's disease or Parkinson's disease in asymptomatic individuals. We argue that further characterization and a deeper understanding of olfactory deficits in these neurodegenerative diseases at the molecular, cellular, and systems levels will augment our acumen for preclinical detection and elucidate pathogenic mechanisms to guide the development of new therapeutic modalities.     

Drosophila as a genetic approach to human neurodegenerative disease

Polyglutamine disease is a class of human neurodegenerative diseases characterized by late-onset, progressive neural degeneration. The molecular mechanism is expansion, within the coding region of the respective genes, of a CAG repeat encoding glutamine. The expanded polyglutamine domain confers dominant toxicity on the disease protein, leading to neuronal dysfunction and degeneration. In order to develop Drosophila as a model system to approach and study such human diseases, a human gene encoding an expanded polyglutamine protein was introduced into the fly. Expression of this protein with a pathogenic polyglutamine domain causes late-onset, progressive degeneration of cells in the fly, as it does in humans with disease and mouse transgenic models. Moreover, the protein shows abnormal protein aggregation in flies, similar to human disease tissue. These studies indicate that molecular mechanisms of polyglutamine-induced neurodegeneration are conserved in Drosophila. Through these studies and additional studies to develop fly models for other human neurodegenerative diseases, including Parkinson's disease, the power of Drosophila genetics can be brought to bear toward the molecular understanding and treatment of human neurodegeneration.     

The role of autophagy in neurodegenerative diseases

Autophagy is a process where cytoplasmic components of the cell are transported into the lysosomes and degraded. Autophagy is a complex process that is necessary for the normal functioning of any eukaryotic cell. The neurons are among the cells that are the most sensitive to dysfunction of autophagy. Impaired autophagy at different stages leads to a wide variety of neurodegenerative diseases. In this review, we discuss the stages and underlying molecular mechanisms of autophagy in detail and present the data that concern how impairments at one or more of these stages lead to the development of neurodegenerative diseases. The possibility of applying different therapeutic strategies of autophagy modulation for treatment of neurodegenerative diseases is discussed.     

Promises and challenges in developing RNAi as a research tool and therapy for neurodegenerative diseases

RNA interference (RNAi) is a recently discovered mechanism that is conserved in a wide range of eukaryotic species. Triggered by double-stranded RNA, RNAi identifies and destroys the mRNA that shares homology with the double-stranded RNA. Because of its specificity, RNAi has a high potential for being a powerful investigative and therapeutic tool. Indeed, its use as a reverse genetics tool to determine gene functions in invertebrates and cultured mammalian cells has already been experiencing an explosive growth. Gratifyingly we have also seen its application in dissecting neurodegeneration pathways in vitro. Although early studies suggested that RNAi could be readily adapted for in vivo studies in mammals using the transgenic technology, difficulties including low transgenicity and low RNAi efficacy have emerged, which has prevented the wide use of transgenic RNAi. The potential of RNAi therapy for human diseases has been a great source of excitement. Several new studies have demonstrated this concept in animal models of neurodegenerative disease. In this review, we highlight the recent literature and our own data in applying RNAi in research and therapy in the area of neurodegenerative diseases. We discuss the present and future challenges in the full realization of the potential for RNAi.     

Control of neuroinflammation as a therapeutic strategy for amyotrophic lateral sclerosis and other neurodegenerative disorders

Neurodegenerative diseases, Alzheimer's and Parkinson's diseases, and amyotrophic lateral sclerosis (ALS) are progressive and devastating disorders of the nervous system without cure. Although a number of distinct, but not mutually exclusive, mechanisms can affect disease pathogenesis, neuroinflammation stands in common. Neuroinflammatory responses occur as a consequence of oxidative and excitotoxic neuronal damage, mitochondrial dysfunction, and protein aggregation. Thus, it is believed drugs that modulate inflammation may combat disease progression. Such strategies include those commented on in the report by Arie Neymotin et al. demonstrating lenalidomide's anti-inflammatory and neuroprotective responses in the G93A mutant superoxide dismutase-1 mouse model of ALS (Neymotin et al., 2009). While anti-inflammatory interventions may be required, they may not be sufficient to positively affect clinical outcomes. The targeting of combinations of pathogenic events including clearance of disaggregated proteins together with neuroprotective and immune modulatory strategies may all be required to facilitate positive therapeutic outcomes. This may include the targeting of both innate and adaptive neurotoxic immune responses. This commentary is designed to summarize the promises and perils in achieving immunoregulation for brain homeostatic responses and inevitable therapeutic gain. Promising new ways to optimize immunization schemes and measure their clinical efficacy are discussed with a particular focus on ALS.     

Intravitreal stem cell paracrine properties as a potential neuroprotective therapy for retinal photoreceptor neurodegenerative diseases

Retinal degenerations are the leading causes of irreversible visual loss worldwide. Many pathologies included under this umbrella involve progressive degeneration and ultimate loss of the photoreceptor cells, with age-related macular degeneration and inherited and ischemic retinal diseases the most relevant. These diseases greatly impact patients' daily lives, with accompanying marked social and economic consequences. However, the currently available treatments only delay the onset or slow progression of visual impairment, and there are no cures for these photoreceptor diseases. Therefore, new therapeutic strategies are being investigated, such as gene therapy, optogenetics, cell replacement, or cell-based neuroprotection. Specifically, stem cells can secrete neurotrophic, immunomodulatory, and anti-angiogenic factors that potentially protect and preserve retinal cells from neurodegeneration. Further, neuroprotection can be used in different types of retinal degenerative diseases and at different disease stages, unlike other potential therapies. This review summarizes stem cell-based paracrine neuroprotective strategies for photoreceptor degeneration, which are under study in clinical trials, and the latest preclinical studies. Effective retinal neuroprotection could be the next frontier in photoreceptor diseases, and the development of novel neuroprotective strategies will address the unmet therapeutic needs.     

Growth-factor gene therapy for neurodegenerative disorders

Preclinical neuroscience has advanced rapidly over the past two decades. New approaches for treating neurological disease, including gene-based therapies, nervous-system growth factors, stem cells, novel vaccines, and modulation of the immune system, offer the potential to prevent cell loss and degeneration in the brain, rather than attempting to compensate for loss after it has occurred. I will review one of these prospective therapies: growth-factor gene therapy for Alzheimer's disease, an approach that is currently the subject of a phase I clinical trial. Other disease targets for gene therapy will also be discussed, including Parkinson's disease, Huntington's disease, inborn errors of metabolism, and cancer. The progress of gene-therapy clinical trials is aiding the transition to molecular and gene-targeted therapeutic approaches which have the potential to improve dramatically the prognosis of neurological disease.     

Gene transfer therapy for neurodegenerative disorders

Recent advances in gene transfer technology have led to promising new therapies for neurodegenerative disorders. This article will review methods of gene transfer therapy and applications of these techniques to both genetic and sporadic neurodegenerative illnesses. The article will focus on Parkinson's disease, Huntington's disease, and Alzheimer's disease. Several promising gene therapy approaches to these diseases are being pursued both in animal models and in early human trials. Initial safety–tolerability results from these trials appear promising. It is therefore likely that the number of human trials of gene therapy for neurodegenerative disorders will increase over the coming years. © 2007 Movement Disorder Society     

Essential tremor is a neurodegenerative disease

There are many lines of evidence supporting the idea that essential tremor is more than simply a monosymptomatic disorder and that all the clinical manifestations of this frequent disorder are sustained by a neurodegenerative process. The most important lines of evidence in favor of a neurodegenerative nature of essential tremor are: the anatomic and neuroimaging data demonstrating a pathologic process involving the cerebellum and/or brainstem; the progression of symptom severity with disease duration; and the lack of spontaneous remission of this condition. All of this evidence is supported by recent studies that are summarized in this review.     

AIMP1 deficiency presents as a cortical neurodegenerative disease with infantile onset

We report the second family with AIMP1 deficiency, due to a homozygous truncating AIMP1 (g.107248613 C?>?T) mutation. This female showed early-onset developmental arrest, intractable epileptic spasms, microcephaly, and a rapid clinical course leading to premature death, associated with cerebral atrophy and myelin deficiency on brain MRI. Clinical and neuroimaging findings are consistent with a primary neuronal degenerative disorder, rather than with the previously reported Perlizaeus-Merzbacher-like phenotype. Given its critical role in neurofilament assembly 16, impaired myelin formation is due to neuronal/axonal dysfunction. We propose that AIMP1 deficiency be added to the differential diagnosis of infantile onset, progressive neurodegenerative disease.     

Mitochondrial autophagy in neural function, neurodegenerative disease, neuron cell death, and aging

Macroautophagy is a cellular process by which cytosolic components and organelles are degraded in double-membrane bound structures upon fusion with lysosomes. A pathway for selective degradation of mitochondria by autophagy, known as mitophagy, has been described, and is of particular importance to neurons, because of the constant need for high levels of energy production in this cell type. Although much remains to be learned about mitophagy, it appears that the regulation of mitophagy shares key steps with the macroautophagy pathway, while exhibiting distinct regulatory steps specific for mitochondrial autophagic turnover. Mitophagy is emerging as an important pathway in neurodegenerative disease, and has been linked to the pathogenesis of Parkinson's disease through the study of recessively inherited forms of this disorder, involving PINK1 and Parkin. Recent work indicates that PINK1 and Parkin together maintain mitochondrial quality control by regulating mitophagy. In the Purkinje cell degeneration (pcd) mouse, altered mitophagy may contribute to the dramatic neuron cell death observed in the cerebellum, suggesting that over-active mitophagy or insufficient mitophagy can both be deleterious. Finally, mitophagy has been linked to aging, as impaired macroautophagy over time promotes mitochondrial dysfunction associated with the aging process. Understanding the role of mitophagy in neural function, neurodegenerative disease, and aging represents an essential goal for future research in the autophagy field. This article is part of a Special Issue entitled "Autophagy and protein degradation in neurological diseases."     

Novel therapeutic strategies for neurodegenerative disease

The activity of protein phosphatase 2A (PP2A) is compromised and believed to be the cause of the abnormal hyperphosphorylation of tau in Alzheimer's disease (AD) brain. Activity of PP2A is regulated by two endogeneous inhibitor proteins, called as I₁^PP2A and I₂^PP2A. Previously, we reported that: (i) I₁^PP2A and I₂^PP2A are upregulated with cleavage of I₂^PP2A holoprotein and translocation of its amino terminal fragment from the nucleus to the cytoplasm in neuronal cells in AD brains; and (ii) translocated I₂^PP2A colocalized not only with the PP2A catalytic subunit, but also with phosphorylated tau in neuronal cytoplasm. Furthermore, according to preliminary data, the cleavage site of I₂^PP2A is located between amino acids 175 and 176 of the I₂^PP2A sequence. Because the sequence from amino acids 168 to 181 on I₂^PP2A presumably functions as a nuclear localization signal (NLS), inhibition of break down of the NLS in I₂^PP2A is expected to be a novel therapeutic target for the treatment of Alzheimer's disease.     

Mouse models as a tool for understanding neurodegenerative diseases

PURPOSE OF REVIEW: The purpose of this review is to present recent advances in the both the creation and the use of mouse models of human neurodegenerative disease. We briefly touch on the technologies used to make these models, and then focus on recent results from new models. We discuss why such models are useful when they do - and do not - mimic the human disorder. RECENT FINDINGS: The numbers of mouse models are increasing dramatically and are starting to yield important results for human disease. We present a selection of new and important models and the results of recent investigations of these animals. SUMMARY: An accepted protocol when studying any form of human neurodegenerative disease is to investigate the genetics, pathology, neurophysiology, response to therapeutics, etc., of the disorder in the mouse. This approach is clearly bearing fruit for our understanding and treatment of human neurodegeneration.     

JNK3 as a therapeutic target for neurodegenerative diseases

c-Jun N-terminal kinases (JNKs) and in particular JNK3 the neuronal specific isoform, have been recognized as important enzymes in the pathology of diverse neurological disorders. Indeed, several efforts have been made to design drugs that inhibit JNK signaling. The success that characterized the new generation of cell permeable peptides raise the hope in the field of neurodegeneration for new therapeutic routes. However, in order to design new and more efficient therapeutical approaches careful re-examination of current knowledge is required. Scaffold proteins are key endogenous regulators of JNK signaling: they can modulate spatial and temporal activation of the JNK signaling and can thus provide the basis for the design of more specific inhibitors. This review focuses on delineating the role of scaffold proteins on the regulation of JNK signaling in neurons. Furthermore the possibility to design a new JNK3 cell permeable peptide inhibitor by targeting the β-arrestin-JNK3 interaction is discussed.     

Prospects for redox-based therapy in neurodegenerative diseases

Accumulating evidence supports a primary role for perturbations in redox metabolism in the pathogenesis of many neurodegenerative diseases. This evidence derives mainly from molecular genetic analysis, direct observation from post-mortem human brain, and biochemical, pathologic, and therapeutic studies in transgenic and other animal models of neurodegeneration. We review here the evidence for redox-mediated pathogenesis in neurodegenerative diseases. The emerging class of redox-based therapeutic agents is then discussed. Drugs of this class are distinguished by their proximate effect, which is oxidative and not phosphorylative.