Recent progress in the applications of presynaptic dopaminergic positron emission tomography imaging in parkinsonism

Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism.This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism.We conducted a thorough literature search using reputable databases such as PubMed and Web of Science.Selection criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical applications.The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis.Moreover,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker.This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion.In summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.

SYNGR4 and PLEKHB1 deregulation in motor neurons of amyotrophic lateral sclerosis models: potential contributions to pathobiology

Amyotrophic lateral sclerosis is the most common adult-onset neurodegenerative disease affecting motor neurons. Its defining feature is progressive loss of motor neuron function in the cortex, brainstem, and spinal cord, leading to paralysis and death. Despite major advances in identifying genes that can cause disease when mutated and model the disease in animals and cellular models, it still remains unclear why motor symptoms suddenly appear after a long pre-symptomatic phase of apparently normal function. One hypothesis is that age-related deregulation of specific proteins within key cell types, especially motor neurons themselves, initiates disease symptom appearance and may also drive progressive degeneration. Genome-wide in vivo cell-type-specific screening tools are enabling identification of candidates for such proteins. In this minireview, we first briefly discuss the methodology used in a recent study that applied a motor neuron-specific RNASeq screening approach to a standard model of TAR DNA-binding protein-43(TDP-43)-driven amyotrophic lateral sclerosis. A key finding of this study is that synaptogyrin-4 and pleckstrin homology domain-containing family B member 1 are also deregulated at the protein level within motor neurons of two unrelated mouse models of mutant TDP-43 driven amyotrophic lateral sclerosis. Guided by what is known about molecular and cellular functions of these proteins and their orthologs, we outline here specific hypotheses for how changes in their levels might potentially alter cellular physiology of motor neurons and detrimentally affect motor neuron function. Where possible, we also discuss how this information could potentially be used in a translational context to develop new therapeutic strategies for this currently incurable, devastating disease.

The molecular chaperone Hsp90α deficiency causes retinal degeneration by disrupting Golgi organization and vesicle transportation in photoreceptors

Heat shock protein 90(Hsp90)is an abundant molecular chaperone with two isoforms,Hsp90α and Hsp90p.Hsp90β deficiency causes embryonic lethality,whereas Hsp90α deficiency causes few abnormities except male sterility.In this paper,we reported that Hsp90α was exclusively expressed in the retina,testis,and brain.Its deficiency caused retinitis pigmentosa(RP),a disease leading to blindness.In Hsp90α-deficient mice,the retina was deteriorated and the outer segment of photoreceptor was deformed.Immunofluorescence staining and electron microscopic analysis revealed disintegrated Golgi and aberrant intersegmental vesicle transportation in Hsp90α-deficient photoreceptors.Proteomic analysis identified microtubule-associated protein IB(MAP1B)as an Hsp90α-associated protein in photoreceptors.Hspcx deficiency increased degradation of MAP1B by inducing its ubiquitination,causing a-tubulin deacetylation and microtubule destabilization.Furthermore,the treatment of wild-type mice with 17-DMAG,an Hsp90 inhibitor of geldanamycin derivative,induced the same retinal degeneration as Hsp90α deficiency.Taken together,the microtubule destabilization could be the underlying reason for Hsp90α deficiency-induced RP.

Advances in understanding the roles of actin scaffolding and membrane trafficking in dendrite development

Dendritic morphology is typically highly branched,and the branching and synaptic abundance of dendrites can enhance the receptive range of neurons and the diversity of information received,thus providing the basis for information processing in the nervous system.Once dendritic development is aberrantly compromised or damaged,it may lead to abnormal connectivity of the neural network,affecting the function and stability of the nervous system and ultimately triggering a series of neurological disorders.Research on the regulation of dendritic developmental processes has flourished,and much progress is now being made in its regulatory mechanisms.Noteworthily,dendrites are characterized by an extremely complex dendritic arborization that cannot be attributed to individual protein functions alone,requiring a systematic analysis of the intrinsic and extrinsic signals and the coordinated roles among them.Actin cytoskeleton organization and membrane vesicle trafficking are required during dendrite development,with actin providing tracks for vesicles and vesicle trafficking in turn providing material for actin assembly.In this review,we focus on these two basic biological processes and discuss the molecular mechanisms and their synergistic effects underlying the morphogenesis of neuronal dendrites.We also offer insights and discuss strategies for the potential preventive and therapeutic treatment of neuropsychiatric disorders.

Protein trafficking during plant innate immunity

Plants have evolved a sophisticated immune system to fight against pathogenic microbes. Upon detection of pathogen invasion by immune receptors, the immune system is turned on, resulting in production of antimicrobial molecules including pathogenesis-related（PR） proteins.Conceivably, an efficient immune response depends on the capacity of the plant cell＇s protein/membrane trafficking network to deploy the right defense-associated molecules in the right place at the right time. Recent research in this area shows that while the abundance of cell surface immune receptors is regulated by endocytosis, many intracellular immune receptors, when activated, are partitioned between the cytoplasm and the nucleus for induction of defense genes and activation of programmed cell death, respectively. Vesicle transport is an essential process for secretion of PR proteins to the apoplastic space and targeting of defense-related proteins to the plasma membrane or other endomembrane compartments. In this review, we discuss the various aspects of protein trafficking during plant immunity, with a focus on the immunity proteins on the move and the major components of the trafficking machineries engaged.

Diverse cellular strategies for the export of leaderless proteins

Unconventional protein export/secretion(UPE/UPS),in contrast to the classical ER-Golgi-dependent export/secretion of proteins with a leader sequence(signal peptide),employs multiple means to release leaderless cargoes(and in some special cases,cargoes with a leader sequence)to the extracellular space.By far,two major types of UPE have been classified,vesicle-independent UPE and vesicle-dependent UPE.In the former,UPE cargoes can directly translocate across the plasma membrane from the cytoplasm without the assistance of a vesicle carrier.In the latter,UPE cargoes translocate into the lumen of a vesicle which then delivers them out of the cell through membrane trafficking.Both types of UPE require multiple unconventional solutions to complete secretion.Here,we briefly discuss the multiple strategies for a UPE cargo release,focusing on two key steps of leaderless cargoes release in UPE:protein translocation and membrane trafficking.

Cell biology and immunology lessons taught by Legionella pneumophila

Legionella pneumophila is a facultative intracellular pathogen capable of replicating within a broad range of hosts. One unique feature of this pathogen is the cohort of ca. 300 virulence factors(effectors) delivered into host cells via its Dot/Icm type IV secretion system. Study of these proteins has produced novel insights into the mechanisms of host function modulation by pathogens, the regulation of essential processes of eukaryotic cells and of immunosurveillance. In this review, we will briefly discuss the roles of some of these effectors in the creation of a niche permissive for bacterial replication in phagocytes and recent advancements in the dissection of the innate immune detection mechanisms by challenging immune cells with L. pneumophila.