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author:("Kao, aimed W.")
1.  Cognitive and Neuropsychiatric Profile of the Synucleinopathies: Parkinson's Disease, Dementia with Lewy Bodies and Multiple System Atrophy 
Parkinson's Disease (PD), multiple system atrophy (MSA) and dementia with Lewy Bodies (DLB) share α-synuclein immunoreactivity 1. These “synucleinopathies” have overlapping signs and symptoms, but less is known about similarities and differences in their cognitive and neuropsychiatric profiles. We compared the cognitive and neuropsychiatric profiles of individuals with PD, MSA and DLB. Overall, the DLB group showed the most cognitive impairment, the MSA group demonstrated milder impairment and the PD group was the least cognitively impaired. The DLB and MSA groups showed worse executive function and visuospatial skills than PD, while DLB showed impaired memory relative to both PD and MSA. On the neuropsychiatric screening, all groups endorsed depression and anxiety; the DLB group alone endorsed delusions and disinhibition. Consistent with their greater level of cognitive and neuropsychiatric impairment, the DLB group showed the greatest amount of functional impairment on a measure of instrumental ADLs (FAQ). We found that MSA subjects had cognitive difficulties that fell between the mild deficits of the PD group and the more severe deficits of the DLB group. PD, MSA and DLB groups have similar neuropsychiatric profiles of increased depression and anxiety. Similar underlying α-synuclein pathology may contribute to these shared features.
PMCID: PMC2886667  PMID: 19935145
Parkinson's Disease; Dementia with Lewy Bodies; multiple system atrophy; dementia; alpha-synuclein
2.  The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels 
The Journal of Neuroscience  2015;35(25):9315-9328.
Mutations in the human progranulin gene resulting in protein haploinsufficiency cause frontotemporal lobar degeneration with TDP-43 inclusions. Although progress has been made in understanding the normal functions of progranulin and TDP-43, the molecular interactions between these proteins remain unclear. Progranulin is proteolytically processed into granulins, but the role of granulins in the pathogenesis of neurodegenerative disease is unknown. We used a Caenorhabditis elegans model of neuronal TDP-43 proteinopathy to specifically interrogate the contribution of granulins to the neurodegenerative process. Complete loss of the progranulin gene did not worsen TDP-43 toxicity, whereas progranulin heterozygosity did. Interestingly, expression of individual granulins alone had little effect on behavior. In contrast, when granulins were coexpressed with TDP-43, they exacerbated its toxicity in a variety of behaviors including motor coordination. These same granulins increased TDP-43 levels via a post-translational mechanism. We further found that in human neurodegenerative disease subjects, granulin fragments accumulated specifically in diseased regions of brain. To our knowledge, this is the first demonstration of a toxic role for granulin fragments in a neurodegenerative disease model. These studies suggest that presence of cleaved granulins, rather than or in addition to loss of full-length progranulin, may contribute to disease in TDP-43 proteinopathies.
PMCID: PMC4478251  PMID: 26109656
C. elegans; frontotemporal lobar degeneration; granulin; neurodegenerative disease; progranulin; TDP-43
3.  A Shift to Organismal Stress Resistance in Programmed Cell Death Mutants 
PLoS Genetics  2013;9(9):e1003714.
Animals have many ways of protecting themselves against stress; for example, they can induce animal-wide, stress-protective pathways and they can kill damaged cells via apoptosis. We have discovered an unexpected regulatory relationship between these two types of stress responses. We find that C. elegans mutations blocking the normal course of programmed cell death and clearance confer animal-wide resistance to a specific set of environmental stressors; namely, ER, heat and osmotic stress. Remarkably, this pattern of stress resistance is induced by mutations that affect cell death in different ways, including ced-3 (cell death defective) mutations, which block programmed cell death, ced-1 and ced-2 mutations, which prevent the engulfment of dying cells, and progranulin (pgrn-1) mutations, which accelerate the clearance of apoptotic cells. Stress resistance conferred by ced and pgrn-1 mutations is not additive and these mutants share altered patterns of gene expression, suggesting that they may act within the same pathway to achieve stress resistance. Together, our findings demonstrate that programmed cell death effectors influence the degree to which C. elegans tolerates environmental stress. While the mechanism is not entirely clear, it is intriguing that animals lacking the ability to efficiently and correctly remove dying cells should switch to a more global animal-wide system of stress resistance.
Author Summary
As an animal interacts with its environment, it invariably encounters stressful conditions such as extreme temperatures, drought, UV exposure and harmful xenobiotics. Since the ability to respond appropriately to stressful stimuli is paramount to survival, organisms have developed sophisticated stress response programs. Some stressful conditions cause damaged cells to commit suicide (undergo apoptosis), whereas others cause the entire organism to develop mechanisms to resist environmental stress. Studying the small roundworm C. elegans, we find that these two responses are somehow linked: perturbing the mechanisms that allow cells to undergo apoptosis changes the whole animal's response to environmental stress. In fact, perturbing the apoptosis machinery in any way—through mutations that prevent apoptosis altogether, or through mutations that either slow or accelerate the clearance of dying cells—causes the animal to become more stress resistant. Together our findings raise the possibility that the animal may have a way of detecting defects in the normal programmed cell death pathway, and that in response it induces a new program that protects itself from a harsh environment.
PMCID: PMC3778000  PMID: 24068943
4.  Dynamin Is Required for Recombinant Adeno-Associated Virus Type 2 Infection 
Journal of Virology  1999;73(12):10371-10376.
Recombinant adeno-associated virus (rAAV) vectors for gene therapy of inherited disorders have demonstrated considerable potential for molecular medicine. Recent identification of the viral receptor and coreceptors for AAV type 2 (AAV-2) has begun to explain why certain organs may demonstrate higher efficiencies of gene transfer with this vector. However, the mechanisms by which AAV-2 enters cells remain unknown. In the present report, we have examined whether the endocytic pathways of rAAV-2 are dependent on dynamin, a GTPase protein involved in clathrin-mediated internalization of receptors and their ligands from the plasma membrane. Using a recombinant adenovirus expressing a dominant-inhibitory form of dynamin I (K44A), we have demonstrated that rAAV-2 infection is partially dependent on dynamin function. Overexpression of mutant dynamin I significantly inhibited AAV-2 internalization and gene delivery, but not viral binding. Furthermore, colocalization of rAAV and transferrin in the same endosomal compartment provides additional evidence that clathrin-coated pits are the predominant pathway for endocytosis of AAV-2 in HeLa cells.
PMCID: PMC113092  PMID: 10559355
5.  Inhibition of Clathrin-Mediated Endocytosis Selectively Attenuates Specific Insulin Receptor Signal Transduction Pathways 
Molecular and Cellular Biology  1998;18(7):3862-3870.
To examine the role of clathrin-dependent insulin receptor internalization in insulin-stimulated signal transduction events, we expressed a dominant-interfering mutant of dynamin (K44A/dynamin) by using a recombinant adenovirus in the H4IIE hepatoma and 3T3L1 adipocyte cell lines. Expression of K44A/dynamin inhibited endocytosis of the insulin receptor as determined by both cell surface radioligand binding and trypsin protection analysis. The inhibition of the insulin receptor endocytosis had no effect on either the extent of insulin receptor autophosphorylation or insulin receptor substrate 1 (IRS1) tyrosine phosphorylation. In contrast, expression of K44A/dynamin partially inhibited insulin-stimulated Shc tyrosine phosphorylation and activation of the mitogen-activated protein kinases ERK1 and -2. Although there was an approximately 50% decrease in the insulin-stimulated activation of the phosphatidylinositol 3-kinase associated with IRS1, insulin-stimulated Akt kinase phosphorylation and activation were unaffected. The expression of K44A/dynamin increased the basal rate of amino acid transport, which was additive with the effect of insulin but had no effect on the basal or insulin-stimulated DNA synthesis. In 3T3L1 adipocytes, expression of K44A/dynamin increased the basal rate of glucose uptake, glycogen synthesis, and lipogenesis without any significant effect on insulin stimulation. Together, these data demonstrate that the acute actions of insulin are largely independent of insulin receptor endocytosis and are initiated by activation of the plasma membrane-localized insulin receptor.
PMCID: PMC108970  PMID: 9632770

Results 1-5 (5)