Parkinson's disease: Mechanisms and models

This work was supported by grants from the National Institutes of Health (R01 AG048814, B.A.B.; RO1 DA15043, B.A.B.; P50 NS38377, V.L.D. and T.M.D.) Christopher and Dana Reeve Foundation (B.A.B.), the Novartis Institute for Biomedical Research (B.A.B.), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (B.A.B.), the JPB Foundation (B.A.B., T.M.D.), the Cure Alzheimer’s Fund (B.A.B.), the Glenn Foundation (B.A.B.), the Esther B O’Keeffe Charitable Foundation (B.A.B.), the Maryland Stem Cell Research Fund (2013-MSCRFII-0105-00, V.L.D.; 2012-MSCRFII-0268-00, T.M.D.; 2013-MSCRFII-0105-00, T.M.D.; 2014-MSCRFF-0665, M.K.). S.A.L. was supported by a postdoctoral fellowship from the Australian National Health and Medical Research Council (GNT1052961), and the Glenn Foundation Glenn Award. L.E.C. was funded by a Merck Research Laboratories postdoctoral fellowship (administered by the Life Science Research Foundation). W.-S.C. was supported by a career transition grant from NEI (K99EY024690). C.J.B. was supported by a postdoctoral fellowship from Damon Runyon Cancer Research Foundation (DRG-2125-12). L.S. was supported by a postdoctoral fellowship from the German Research Foundation (DFG, SCHI 1330/1-1).

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Neurotoxic reactive astrocytes are induced by activated microglia

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

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Astrocytes: biology and pathology

Cell Death During Development of the Nervous System

Mechanisms underlying inflammation in neurodegeneration.

The treatment of neurological disorders with conventional drug therapies, such as L-dopa for Parkinson’s disease, has traditionally been achieved by the administration of the drugs through peripheral routes. However, this approach is hampered by the problem of drug penetration across the blood brain barrier, as well as being relatively non-specific with respect to site of action within the CNS. The discovery of high molecular weight proteins which can affect the development of the CNS and protect against various types of neuronal cell death, has stimulated efforts to explore their use as neuroprotective agents in a variety of pathological conditions [3]. The direct delivery of these large peptides to the CNS can be achieved either by injection through an intracerebral cannula, which then communicates to the outside world, or by implantation of a closed system which has the capacity to continuously release the neuroactive substance. The advantages of an implantable system over pump injection are outlined by the authors and relate largely to practical issues such as the risk of infection associated with an indwelling cannula. Two main approaches have been employed in the development of implantable devices.

https://link.springer.com/content/pdf/10.1007%2F978-3-7091-6323-8_4.pdf

Invited commentary: treatment of diseases of the central nervous system using encapsulated cells, by A. F. Hottinger and P. Aebischer (Advances and Technical Standards in Neurosurgery vol. 25).

Many areas of the brain that exhibit neurodegenerative changes in Alzheimer-type dementias (DAT) appear to be interconnected via neuronal projections. The severity of pathology in the neocortex correlates statistically with known patterns of intracortical connections (Pearson et al., 1985), and the major affected subcortical regions, such as the nucleus basalis, locus coeruleus and dorsal raphe project prominently to the allo- or neocortex (Saper et al., 1987). Observations such as these have led to suggestions that the degeneration in some regions of the brain might be secondary to loss of neurons in other areas, resulting from a loss of target-derived trophic support (Appel, 1981; Hefti, 1983). The evidence that this might be the case is particularly suggestive for cholinergic neurons of the basal forebrain.

Changes in Basal Forebrain Cholinergic Systems Following Excitotoxic Cell Death in the Hippocampus and Cerebral Neocortex

Described here are systems and methods for deriving both spinal motor neurons and brain microvascular endothelial cells from induced pluripotent stem cells using distinct methods and combining them in a chip format. Neurons cultured alone in chip microvolume displayed increased calcium transient function and chip-specific gene expression. When seeded with endothelial cells, interaction further enhanced neural function, elicited vascular-neural interaction, niche gene expression with enhanced in vivo-like signatures arising from the chip co-cultures. Development of novel media formulations further allow for improved readout of differentiation process, by eliminating additives that otherwise confound differentiation processes and resulting phenotypes.

Methods and compositions for spinal cord cells

Induced Pluripotent Stem Cell (Ipsc) technology enables the generation and study of living brain tissue relevant to Parkinson's disease (PD) ex vivo. Utilizing cell lines from PD patients presents a powerful discovery system that links cellular phenotypes observed in vitro with real clinical data. Differentiating patient-derived iPSCs towards a dopaminergic (DA) neural fate revealed that these cells exhibit molecular and functional properties of DA neurons in vitro that are observed to significantly degenerate in the substantia nigra of PD patients. Clinical symptoms that drive the generation of other relevant cell types may also yield novel PD-specific phenotypes in vitro that have the potential to lead to new therapeutic avenues for patients with PD. Due to their early onset and non-familial origin, differentiated nervous tissue from these patients offer a key opportunity to discover neuron subtype-specific pathological mechanisms and importantly interrogate the contribution of their genetic background in susceptibility to PD.

Novel differentiation technique to generate dopaminergic neurons from induced pluripotent stem cells

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Clive N. Svendsen

Papers

Invited commentary: treatment of diseases of the central nervous system using encapsulated cells, by A. F. Hottinger and P. Aebischer (Advances and Technical Standards in Neurosurgery vol. 25).

Changes in Basal Forebrain Cholinergic Systems Following Excitotoxic Cell Death in the Hippocampus and Cerebral Neocortex

Methods and compositions for spinal cord cells

Novel differentiation technique to generate dopaminergic neurons from induced pluripotent stem cells

Author Correction: Regenerative and restorative medicine for eye disease